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WO2018187574A1 - Compositions et procédés de traitement d'infections fongiques - Google Patents

Compositions et procédés de traitement d'infections fongiques Download PDF

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Publication number
WO2018187574A1
WO2018187574A1 PCT/US2018/026261 US2018026261W WO2018187574A1 WO 2018187574 A1 WO2018187574 A1 WO 2018187574A1 US 2018026261 W US2018026261 W US 2018026261W WO 2018187574 A1 WO2018187574 A1 WO 2018187574A1
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Prior art keywords
optionally substituted
compound
independently
formula
pharmaceutically acceptable
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English (en)
Inventor
James M. Balkovec
Thomas P. Brady
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Cidara Therapeutics Inc
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Cidara Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C

Definitions

  • Candida albicans and the filamentous fungus, Aspergillus fumigatus (Bow, Br. J. Haematol., 101 :1 , 1998; Wamock, J. Antimicrob. Chemother., 41 :95, 1998).
  • There are an estimated 200,000 patients per year who acquire nosocomial fungal infections (Beck-Sague et al., J. Infect. Dis., 167:1247, 1993).
  • Also adding to the increase in the numbers of fungal infections is the emergence of Acquired Immunodeficiency Syndrome (AIDS) where virtually all patients become affected with some form of mycoses during the course of the disease (Alexander et al., Drugs, 54:657, 1997; Hood et al., J.
  • AIDS Acquired Immunodeficiency Syndrome
  • drugs for the treatment of fungal infections include amphotericin B, a macrolide polyene that interacts with fungal membrane sterols, flucytosine, a fluoropyrimidine that interferes with fungal protein and DNA biosynthesis, and a variety of azoles (e.g., ketoconazole, itraconazole, and fluconazole) that inhibit fungal membrane-sterol biosynthesis (Alexander et al., Drugs, 54:657, 1997).
  • azoles e.g., ketoconazole, itraconazole, and fluconazole
  • Each agent in this class of compound acts by inhibition of ⁇ -1 ,3-D-glucan synthase, which is a key enzyme in the synthesis of glucan in the cell wall of many fungi. All three of these drugs are made semisynthetically, starting with natural products obtained through fermentation.
  • the echinocandins are a broad group of antifungal agents that typically are composed of a cyclic hexapeptide and lipophilic tail, the latter of which is attached to the hexapeptide core through an amide linkage.
  • many echinocandins are natural products, the clinically relevant members of this class have all been semisynthetic derivatives.
  • the naturally occurring echinocandins possess some degree of anti-fungal activity, they have not been suitable as therapeutics, primarily because of poor aqueous solubility, insufficient potency, and/or hemolytic action.
  • the approved echinocandins are the products of intense efforts to generate derivatives that maintain or improve upon the glucan synthase inhibition, but do not cause the hemolytic effects.
  • the poor aqueous solubility and poor intestinal absorption of these compounds have relegated them to delivery by intravenous infusion. There is a need in the art for improved compounds and methods of treatment for fungal infections.
  • the disclosure relates to compounds, compositions, and methods for the treatment of fungal infections.
  • such compounds include bifunctional molecules including a ⁇ -1 ,3-glucan synthase inhibitor and at least one monosaccharide or oligosaccharide moiety, ⁇ -1 ,3-glucan synthase inhibitors bind to and inhibit the function of ⁇ -1 ,3-glucan synthase, a glucosyltransferase enzyme involved in the generation of ⁇ -glucan in the cell wall of fungi, resulting in disrupting the integrity of the fungal cell well and leading to fungal cell death.
  • Such compounds are useful in methods for the inhibition of fungal growth and in methods for the treatment of fungal infections, such as those caused by a fungus of the genus Candida.
  • the invention features a compound including a ⁇ -1 ,3-glucan synthase inhibitor conjugated to at least one monosaccharide or oligosaccharide moiety by way of a linker, wherein the
  • R 1 is a lipophilic moiety
  • R 2 is hydrogen or methyl
  • each of R 3 and R 4 is, independently, hydrogen or hydroxyl
  • R 5 is hydrogen, methyl, or optionally substituted C1 -C5 alkamino
  • R 6 is hydrogen, hydroxyl, methyl, or amino
  • R 7 is hydrogen or hydroxyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH 2 ) a )bR', -(NH(CH 2 ) a )bR', -(S(CH 2 ) a )bR', -(0(CH 2 ) a ) b N(R') 2 , -(NH(CH 2 ) a ) b N(R') 2 , -(S(CH 2 ) a ) b N(R') 2 , -(0(CH 2 ) a ) b N + (R') 3 ,
  • R 9 is hydrogen, hydroxyl, or amino; n is 0 or 1 ; d is 1 , 2, 3, 4, 5, or 6; each of a and b is, independently, an integer from 1 to 5; each R' is, independently, hydrogen, optionally substituted C1 -C1 0 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyi, optionally substituted C3-
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , n, d, L, and E are as defined above, or a pharmaceutically acceptable salt thereof.
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(O(CH2)a)bR’,
  • each of a and b is, independently, an integer from 1 to 5; d is 1, 2, 3, 4, 5, or 6; each R’ is, independently, hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyi, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1 -C10 heteroaryl; L is a linker; and each E is, independently
  • the invention features a compound including a ⁇ -1 ,3-glucan synthase inhibitor conjugated to at least one monosaccharide or oligosaccharide moiety by way of a linker, wherein the compound is described by formula (II):
  • R 1 is a lipophilic moiety
  • R 2 is hydrogen or methyl
  • each of R 3 and R 4 is, independently, hydrogen or hydroxyl
  • R 6 is hydrogen, hydroxyl, methyl, or amino
  • R 7 is hydrogen or hydroxyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH2) a )bR', -(NH(CH2) a )bR',
  • R 9 is hydrogen, hydroxyl, or amino
  • n is 0 or 1
  • each of a and b is, independently, an integer from 1 to 5
  • d is 1 , 2, 3, 4, 5, or 6
  • each R' is, independently, hydrogen, optionally substituted C1 -C10 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyi, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1 -C10 heteroaryl
  • each R" is, independently, hydrogen or C1 -C10 alkyl
  • L is a linker
  • each E is, independently, a monosaccharide or oligosaccharide mo
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , n, d, L, and E are as defined above, or a pharmaceutically acceptable salt thereof.
  • R 1 is a lipophilic moiety
  • R 6 is hydrogen or methyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH 2 ) a )bR', -(NH(CH 2 ) a )bR', -(S(CH 2 ) a )bR', -(0(CH 2 ) a )bN(R')2,
  • each R' is, independently, hydrogen, optionally substituted C1 -C10 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1 -C10 heteroaryl ; each of R" is, independently, hydrogen or C1 -C10 alkyl; L is a linker; and each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the invention features a compound including a ⁇ -1 ,3-glucan synthase inhibitor conjugated to at least one monosaccharide or oligosaccharide moiety by way of a linker, wherein the compound is described by formula (III):
  • R 1 is a lipophilic moiety
  • R 2 is hydrogen or methyl
  • each of R 3 and R 4 is, independently, hydrogen or hydroxyl
  • R 5 is hydrogen, methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen, hydroxyl, methyl, or amino
  • R 7 is hydrogen or hydroxyl
  • R 9 is hydrogen, hydroxyl, or amino
  • X is O or NH
  • n is 0 or 1
  • d is 1 , 2, 3, 4, 5, or 6
  • L is a linker
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , X, n, d, L, and E are as defined above, or a pharmaceutically acceptable salt thereof.
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • X is O or NH
  • d is 1 , 2, 3, 4, 5, or 6
  • L is a linker
  • each E is, independently, a
  • R 8 is -(0(CH2) a )bR', -(NH(CH 2 ) a )bR', -(S(CH 2 ) a )bR', -(0(CH 2 ) a )bN(R')2, -(NH(CH 2 ) a )bN(R')2, -(S(CH 2 ) a )bN(R')2,
  • each of a and b is, independently, an integer from 1 to 5; and each R' is, independently, hydrogen or optionally substituted C1 -C5 alkyi, or a pharmaceutically acceptable salt thereof.
  • R 8 is -OCH2CH 2 N(R')2, -NHCH2CH 2 N(R')2, -(NHCH 2 CH2)2N(R')2, -NHCH2CH2OR', -(NHCH 2 CH2)20R', -OCH2CH2NHCH2CH 2 N(R')2, -NHCH2CH 2 OCH2CH2N(R')2,
  • each R' is, independently, hydrogen or methyl; or a pharmaceutically acceptable salt thereof.
  • R 8 is -(0(CH2) a )bR', -(NH(CH 2 ) a )bR', -(S(CH 2 ) a )bR', -(0(CH 2 )a)bN(R')2, -(NH(CH 2 )a)bN(R")2, -(S(CH 2 )a)bN(R')2,
  • R 8 is -OCH2CH2N(R')2,
  • each R' is, independently, hydrogen or methyl
  • each R" is, independently, hydrogen or methyl
  • R 8 is
  • R 8 is
  • each of a and b is, independently, an integer from 1 to 5; and each R' is, independently, hydrogen or optionally substituted C1 -C5 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 8 is -OCH2CH 2 N + (R')3, -(OCH 2 CH2)2N + (R')3, -NHCH2CH 2 N + (R')3, or -(NHCH 2 CH2)2N + (R')3; each R' is, independently, hydrogen or methyl, or a pharmaceutically acceptable salt thereof. In some embodiments, R 8 is
  • R' is
  • each R A is, independently, hydrogen or optionally substituted C1 -C1 0 alkyl.
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (I-4) or (I-5):
  • R 1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) is described by formula
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (I-7):
  • R 1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) is described by formula
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (I-9) or (1-10):
  • R 1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof.
  • the compound of formula (II) is described by formula
  • R 1 is a lipophilic moiety
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (II-4):
  • R 1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof.
  • the compound of formula (II) is described by formula
  • R 1 is a lipophilic moiety
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (II-6):
  • R 1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof.
  • the compound of formula (II) is described by formula
  • R 1 is a lipophilic moiety
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (II-8):
  • R 1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof.
  • the compound of formula (III) is described by formula
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (III-4):
  • R 1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof.
  • R 1 is
  • each of X and Y is, independently, optionally substituted alkyl, optionally substituted heteroalkyi, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene, or is absent;
  • Z is optionally substituted alkyl, optionally substituted heteroalkyi, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl,
  • -CH2 CH2-,or a pharmaceutically acceptable salt thereof.
  • R 1 is and X, Y, and Z,
  • R B is an optionally substituted C1 -C10 alkyl, or a
  • R 1 is and X, Y, and Z,
  • R B is optionally substituted C1 -C10 alkyl, or a
  • R 1 is and X, Y, and Z,
  • R B is optionally substituted C1 -C8 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 1 is and X, Y, and Z,
  • R B is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 1 is
  • the compound is described by formula (I-11) or (I-12):
  • R 5 is methyl, -CH2CH2NH2, or -CH 2 (CO)NH 2 ;
  • R 6 is hydrogen or methyl;
  • R B is optionally substituted C1 -C6 alkyl;
  • d is 1 , 2, 3, or 4;
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (1-13) or (1-14):
  • R B is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 5 is methyl, -CH2CH2NH2, or -CH 2 (CO)NH 2 ;
  • R 6 is hydrogen or methyl;
  • d is 1 , 2, 3, or 4;
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (1-16):
  • the compound is described by formula (1-17) or (1-18):
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2;
  • R 6 is hydrogen or methyl;
  • R B is optionally substituted C1 -C6 alkyl;
  • d is 1 , 2, 3, or 4;
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (1-19) or (I-20):
  • R B is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (II-9) or (11-10):
  • R 6 is hydrogen or methyl; R B is optionally substituted C1 -C6 alkyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (11-1 1 ) or (11-12):
  • R B is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (11-13) or (11-14):
  • R 6 is hydrogen or methyl; R B is optionally substituted C1 -C6 alkyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (11-15) or (11-16):
  • R B is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 6 is hydrogen or methyl; and R B is optionally substituted C1 -C6 alkyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (11-19) or (II-20):
  • the compound is described by formula -5) or (111-6):
  • R B is optionally substituted C1 -C6 alkyl
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • L is a bond
  • L is described by formula (L-l):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor
  • I 2 is a bond attached to E
  • U 1 , U 2 , U 3 , and U 4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -
  • V 1 , V 2 , V 3 , V 4 , and V 5 is, independently, O, S, NR.', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl
  • heterocycloalkyl optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl ; and each of f, g, h, i, j, k, I, m, and n is, independently, 0 or 1 .
  • each of U 1 , U 2 , U 3 , and U 4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C1 5 arylene, or optionally substituted C1 -C15 heteroarylene; each of V 1 , V 2 , V 3 , V 4 , and V 5 is,
  • R' is H or optionally substituted C1 -C20 alkyl; and each of f, g, h, i, j, k, I, m, and n is, independently, 0 or 1 .
  • L is described by formula (L- II ):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor
  • I 2 is a bond attached to E
  • L is described by formula (L-I2):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor
  • I 2 is a bond attached to E
  • L is described by formula (L-I3):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor
  • I 2 is a bond attached to E
  • L is described by formula (L-I4):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor; I 2 is a bond attached to E;
  • each of U 1 , U 2 , U 3 , and U 4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C15 arylene, or optionally substituted C1 -C15 heteroarylene; each of V 2 , V 3 , and V 4 is, independently, O, S, NR', P, carbonyl ; R' is H or optionally substituted C1 -C20 alkyl; and each of h, i, j, k, I, and m is, independently, 0 or 1 .
  • L is N
  • each of p, q, r, and s is, independently, an integer from 1 to 10.
  • L is described by formula (L-II):
  • L A is described by formula G A1 -(Z A1 )g1-(Y A1 )h1-(Z A2 )i1-(Y A2 )j1-(Z A3 )k1-(Y A3 )l1-(Z A4 )m1-(Y A4 )n1- (Z A5 )o1-G A2 ;
  • L B is described by formula G B1 -(Z B1 )g2-(Y B1 )h2-(Z B2 )i2-(Y B2 )j2-(Z B3 )k2-(Y B3 )l2-(Z B4 )m2-(Y B4 )n2- (Z B5 )o2-G B2 ;
  • L C is described by formula G C1 -(Z C1 )g3-(Y C1 )h3-(Z C2 )i3-(Y C2 )j3-(Z C3 )k3-(Y C3 )l3-
  • R i is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl; and each of g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h
  • each of Y A1 , Y A2 , Y A3 , Y A4 , Y B1 , Y B2 , Y B3 , Y B4 , Y C1 , Y C2 , Y C3 , and Y C4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C15 arylene, or optionally substituted C1-C15 heteroarylene; each of Z A1 , Z A2 , Z A3 , Z A4 , Z A5
  • L is
  • each of p, q, r, s, and t is, independently, an integer from 1 to 10.
  • L is N
  • L is N
  • each of p, q, r, s, t, and u is, independently, an integer from 1 to 10.
  • L is described by formula (L-III):
  • L A is described by formula G A1 -(Z A1 )g1-(Y A1 )h1-(Z A2 )i1-(Y A2 )j1-(Z A3 )k1-(Y A3 )l1-(Z A4 )m1-(Y A4 )n1- (Z A5 )o1-G A2 ;
  • L B is described by formula G B1 -(Z B1 )g2-(Y B1 )h2-(Z B2 )i2-(Y B2 )j2-(Z B3 )k2-(Y B3 )l2-(Z B4 )m2-(Y B4 )n2- (Z B5 )o2-G B2 ;
  • L C is described by formula G C1 -(Z C1 )g3-(Y C1 )h3-(Z C2 )i3-(Y C2 )j3-(Z C3 )k3-(Y C3 )l3-
  • each of Y A1 , Y A2 , Y A3 , Y A4 , Y B1 , Y B2 , Y B3 , Y B4 , Y C1 , Y C2 , Y C3 , Y C4 , Y D1 , Y D2 , Y D3 , Y D4 , Y E1 , Y E2 , Y E3 , Y E4 , Y F1 , Y F2 , Y F3 , Y F4 , Y G1 , Y G2 , Y G3 , and Y G4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2- C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-
  • L is N
  • each of p, q, r, s, t, u, v, w, x, y, and z is, independently, an integer from 1 to 10.
  • L is N
  • L is
  • each of p, q, r, s, and t is, independently, an integer from 1 to 10.
  • L is described by formula (L-IV):
  • L A is described by formula G A1 -(Z A1 )g1-(Y A1 )h1-(Z A2 )i1-(Y A2 )j1-(Z A3 )k1-(Y A3 )l1-(Z A4 )m1-(Y A4 )n1- (Z A5 )o1-G A2 ;
  • L B is described by formula G B1 -(Z B1 )g2-(Y B1 )h2-(Z B2 )i2-(Y B2 )j2-(Z B3 )k2-(Y B3 )l2-(Z B4 )m2-(Y B4 )n2- (Z B5 )o2-G B2 ;
  • L C is described by formula G C1 -(Z C1 )g3-(Y C1 )h3-(Z C2 )i3-(Y C2 )j3-(Z C3 )k3-(Y C3 )l3-
  • G C2 is a bond attached to a second monosaccharide or oligosaccharide moiety, E 2 ;
  • G D1 is a bond attached to C in formula (L-IV);
  • G D2 is a bond attached to a third monosaccharide or oligosaccharide moiety, E 3 ;
  • each of Y A1 , Y A2 , Y A3 , Y A4 , Y B1 , Y B2 , Y B3 , Y B4 , Y C1 , Y C2 , Y C3 , Y C4 , Y D1 , Y D2 , Y D3 , and Y D4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkyny
  • L is N
  • each of p, q, r, s, and t is, independently, an integer from 1 to 10.
  • E is
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • the monosaccharide moiety includes an optionally substituted C6-C9 monosaccharide residue. In some embodiments of the compounds described herein, the oligosaccharide moiety includes 2-18 optionally substituted C6-C9 monosaccharide residues.
  • each of the optionally substituted C6-C9 monosaccharide residues is, independently, glucose (Glc), galactose (Gal), mannose (Man), allose (All), altrose (Alt), gulose (Gul), idose (Ido), talose (Tal), fucose (Fuc), rhamnose (Rha or L-Rha), thia-rhamnose (thia-Rha or thia-L- Rha), quinovose (Qui), 2-deoxyglucose (2-dGlc), glucosamine (GlcN), galactosamine (GaIN), mannosamine (ManN), fucosamine (FucN), quinovosamine (QuiN), N-Acetyl-glucosamine (GlcNAc), N-Acetyl-galactosamine (GalNAc), N-Acetyl-mannosamine (ManNAc), N-acety
  • each of the optionally substituted C6-C9 monosaccharide residues is, independently, an optionally substituted C6 monosaccharide residue
  • the optionally substituted C6 monosaccharide residue is
  • E is any one of the moieties in Tables 2A and 2B.
  • E directly or indirectly activates an immune cell.
  • a concentration of the compound, or a pharmaceutically acceptable salt thereof, that activates an immune cell is less than or equal to 10,000 nM.
  • the concentration of the compound, or a pharmaceutically acceptable salt thereof, that activates an immune cell is less than or equal to equal to 1 ,000 nM.
  • the concentration of the compound, or a pharmaceutically acceptable salt thereof, that activates an immune cell is less than or equal to equal to 100 nM.
  • E is a ligand to an innate immune receptor.
  • the innate immune receptor is AICL, BDCA2, CLEC2, Complement receptor 3, Complement receptor 4, DCIR, dectin-1 , dectin-2, DC-SIGN, a C-Type lectin receptor, MMR, langerin, TLR2, Mincle, MBL, or KCR.
  • E binds to an antibody.
  • the antibody is a natural antibody (e.g., an antibody of the immunoglobulin M (IgM) isotype).
  • the antibody is anti-aGal antibody or anti-aRha antibody.
  • E binds to an antibody and is any one of the moieties in Tables 2A and 2B.
  • the invention features a compound selected from
  • the pharmaceutically acceptable salt of any one of Compounds 1 -3, 4a, 4b, 5a-5c, and 6 is a formate salt.
  • the compound is Compound 1 ,
  • the pharmaceutically acceptable salt of Compound 1 is a formate salt. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is an acetate salt.
  • the compound is Compound 4a
  • the pharmaceutically acceptable salt of Compound 4a is a formate salt. In some embodiments, the pharmaceutically acceptable salt of Compound 4a is an acetate salt.
  • the invention features a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the invention features a method of treating a fungal infection in a subject by administering to the subject a pharmaceutical composition including a compound described herein in an amount sufficient to treat the infection.
  • the invention features a method of stabilizing or inhibiting a fungal infection in a subject by administering to the subject a pharmaceutical composition including a compound described herein in an amount sufficient to stabilize or inhibit the infection.
  • the subject is immunocompromised.
  • the pharmaceutical composition is administered intravenously. In some embodiments, the pharmaceutical composition is administered subcutaneously. In some embodiments, the pharmaceutical composition is administered topically. In some embodiments, the pharmaceutical composition is administered orally.
  • the pharmaceutical composition is administered to treat a blood stream infection or tissue infection in the subject.
  • the infection is selected from candidemia, invasive candidiasis, tinea capitis, tinea corporis, tinea pedis, onychomycosis, perionychomycosis, pityriasis versicolor, oral thrush, vaginal candidiasis, respiratory tract candidiasis, biliary candidiasis, eosophageal candidiasis, urinary tract candidiasis, systemic candidiasis, mucocutaneous candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis, or chronic sinusitis.
  • the infection is candidemia or invasive candidiasis.
  • the fungal infection is an infection of Candida albicans, C. parapsilosis, C. glabrata, C. guilliermondii, C. krusei, C. tropicalis, C. lusitaniae, Aspergillus fumigatus, A. flavus, A. terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus.
  • the fungal infection is an infection of
  • Exserohilum longirostratum or Exserohilum mcginnisii.
  • the fungal infection is a
  • the pharmaceutical composition includes any one of Compounds 1 -6, or a pharmaceutically acceptable salt thereof.
  • the invention also features a method of stabilizing or inhibiting the growth of fungi, or killing fungi, the method including contacting the fungi or a site susceptible to fungal growth with a compound described herein, or a pharmaceutically acceptable salt thereof.
  • covalently attached refers to two parts of a compound that are linked to each other by a covalent bond formed between two atoms in the two parts of the compound.
  • L serves as a linker that covalently attaches a ⁇ -1 ,3-glucan synthase inhibitor to at least one monosaccharide or oligosaccharide moiety.
  • An amine group in the ⁇ -1 ,3-glucan synthase inhibitor may for an amide bond with a carboxylic acid in the linker and a carbon atom in the monosaccharide or oligosaccharide moiety may form a C-0 bond with an oxygen atom in the linker.
  • linker and “L,” as used herein, refer to a covalent linkage or connection between two or more components in a compound (e.g., the ⁇ -1 ,3-glucan synthase inhibitor and one or more monosaccharide or oligosaccharide moieties in a compound described herein).
  • a compound e.g., the ⁇ -1 ,3-glucan synthase inhibitor and one or more monosaccharide or oligosaccharide moieties in a compound described herein.
  • a compound described herein may contain a linker that has a divalent structure (e.g., a divalent linker), in which one terminus of the linker is conjugated to the ⁇ -1 ,3-glucan synthase inhibitor and the other terminus of the linker is conjugated to a monosaccharide or oligosaccharide moiety.
  • a compound described herein may contain a linker that has a trivalent structure (e.g., a trivalent linker).
  • a trivalent linker has three arms, in which each arm is conjugated to a component of the compound (e.g., a first arm conjugated to the ⁇ -1 ,3-glucan synthase inhibitor, a second arm conjugated to a first monosaccharide or oligosaccharide moiety, and a third arm conjugated to a second monosaccharide or oligosaccharide moiety).
  • a component of the compound e.g., a first arm conjugated to the ⁇ -1 ,3-glucan synthase inhibitor, a second arm conjugated to a first monosaccharide or oligosaccharide moiety, and a third arm conjugated to a second monosaccharide or oligosaccharide moiety.
  • Molecules that may be used as linkers include at least two functional groups, which may be the same or different, e.g., two carboxylic acid groups, two amine groups, two sulfonic acid groups, a carboxylic acid group and an amine group, or a carboxy group and a sulfonic acid group.
  • the first functional group may form a covalent linkage with a first component in the compound and the second functional group may form a covalent linkage with the second component in the compound.
  • the first arm of the linker may contain a dicarboxylic acid that can form a form a covalent linkage (e.g., an amide bond) with the ⁇ -1 ,3-glucan synthase inhibitor
  • the second arm of the linker may for a covalent linkage (e.g., a C-0 bond) with a first monosaccharide or oligosaccharide moiety in the compound
  • the third arm of the linker may for a covalent linkage (e.g., a C-0 bond) with a second monosaccharide or oligosaccharide moiety in the compound.
  • the divalent linker may contain two carboxylic acids, in which the first carboxylic acid may form a covalent linkage with one component (e.g., the ⁇ -1 ,3-glucan synthase inhibitor) in the compound and the second carboxylic acid may form a covalent linkage with another component (e.g., the monosaccharide or oligosaccharide moiety) in the compound.
  • one component e.g., the ⁇ -1 ,3-glucan synthase inhibitor
  • another component e.g., the monosaccharide or oligosaccharide moiety
  • a molecule containing one or more sulfonic acid groups may be used as a linker, in which the sulfonic acid group may form a sulfonamide linkage with a component in the compound.
  • a molecule containing one or more isocyanate groups may be used as a linker, in which the isocyanate group may form a urea linkage with a component in the compound.
  • a molecule containing one or more haloalkyl groups may be used as a linker, in which the haloalkyl group may form a covalent linkage, e.g., C-N and C-0 linkages, with a component in the compound.
  • a linker provides space, rigidity, and/or flexibility between the two or more components.
  • a linker may be a bond, e.g., a covalent bond.
  • the term "bond" refers to a chemical bond, e.g., an amide bond, a disulfide bond, a C-0 bond, a C-S bond, a C-0 bond, a N-N bond, or any kind of bond created from a chemical reaction, e.g., chemical conjugation.
  • a linker includes no more than 250 atoms (e.g., no more than 225, 200, 175, 1 50, 125, 100, 50, 25, 20, 15, or 10 atoms).
  • a linker includes no more than 250 non-hydrogen atoms (e.g., no more than 225, 200, 1 75, 150, 125, 100, 50, 25, 20, 15, or 10 non-hydrogen atoms).
  • the backbone of a linker includes no more than 250 atoms (e.g., no more than 225, 200, 175, 1 50, 125, 1 00, 50, 25, 20, 15, or 10 atoms).
  • the "backbone" of a linker refers to the atoms in the linker that together form the shortest path from one part of a compound to another part of the compound (e.g., the shortest path linking a ⁇ -1 ,3-glucan synthase inhibitor and a monosaccharide or oligosaccharide moiety).
  • the atoms in the backbone of the linker are directly involved in linking one part of a compound to another part of the compound (e.g., linking a ⁇ -1 ,3-glucan synthase inhibitor and a monosaccharide or oligosaccharide moiety).
  • hydrogen atoms attached to carbons in the backbone of the linker are not considered as directly involved in linking one part of the compound to another part of the compound.
  • a linker may include a synthetic group derived from, e.g., a synthetic polymer (e.g., a polyethylene glycol (PEG) polymer).
  • a linker may include one or more amino acid residues, such as D- or L-amino acid residues.
  • a linker may be a residue of an amino acid sequence (e.g., a 1 -25 amino acid, 1 -10 amino acid, 1 -9 amino acid, 1 -8 amino acid, 1 -7 amino acid, 1 -6 amino acid, 1 -5 amino acid, 1 -4 amino acid, 1 -3 amino acid, 1 -2 amino acid, or 1 amino acid sequence).
  • a linker may include one or more, e.g., 1 -100, 1 -50, 1 -25, 1 -10, 1 -5, or 1 -3, optionally substituted alkylene, optionally substituted heteroalkylene (e.g., a PEG unit), optionally substituted alkenylene, optionally substituted
  • heteroalkenylene optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted cycloalkenylene, optionally substituted heterocycloalkenylene, optionally substituted cycloalkynylene, optionally substituted heterocycloalkynylene, optionally substituted arylene, optionally substituted heteroarylene (e.g., pyridine), O, S, NR' (R' is H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkenyl, optionally substituted cycloalkynyl, optionally
  • a linker may include one or more optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene (e.g., a PEG unit), optionally substituted C2-C20 alkenylene (e.g., C2 alkenylene), optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene (e.g., cyclopropylene, cyclobutylene), optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene (e
  • lipophilic moiety refers to a portion, substituent, or functional group of a compound that is, in general, hydrophobic and non-polar.
  • a moiety is lipophilic if it has a hydrophobicity determined using a cLogP value of greater than 0, such as about 0.25 or greater, about 0.5 or greater, about 1 or greater, about 2 or greater, 0.25-5, 0.5-4 or 2-3.
  • cLogP refers to the calculated partition coefficient of a molecule or portion of a molecule.
  • the partition coefficient is the ratio of concentrations of a compound in a mixture of two immiscible phases at equilibrium (e.g., octanol and water) and measures the hydrophobicity or hydrophilicity of a compound.
  • cLogP can be determined using quantitative structure-property relationship algorithms known in the art (e.g., using fragment based prediction methods that predict the logP of a compound by determining the sum of its non-overlapping molecular fragments).
  • a moiety is considered lipophilic if it has a cLogP value described above in at least one of the above methods.
  • a lipophilic moiety having the stated cLogP value will be considered lipophilic, even though it may have a positive charge or a polar substituent.
  • a lipophilic moiety contains entirely hydrocarbons.
  • a lipophilic moiety may contain one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms, wherein each heteroatom is, independently, selected from N, O, and S (e.g., an indolyl), or one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, halo groups, which, due to the structure of the moiety and/or small differences in electronegativity between the heteroatoms or halo groups and the hydrocarbons, do not induce significant chemical polarity into the lipophilic moiety.
  • a lipophilic moiety having, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms and/or, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, halo atoms may still be considered non-polar.
  • a lipophilic moiety may be optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, or optionally substituted heteroaryl, or halo forms thereof, wherein the optional substituents are also lipophilic (such as alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
  • heteroalkynyl, aryl, or heteroaryl or are not lipophilic but do not change the overall lipophilic character of the moiety, i.e., the moiety has a cLogP value of greater than 0.
  • octanol contains a polar group, OH, but is still a lipophilic moiety.
  • a lipophilic moiety may be benzyl, isobutyl, sec-butyl, isopropyl, n-propyl, methyl, biphenylmethyl, n-octyl, or substituted indolyl (e.g., alkyl substituted indolyl).
  • a lipophilic moiety may be the side chain of a hydrophobic amino acid residue, e.g., leucine, isoleucine, alanine, phenylalanine, valine, and proline, or groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and pyrrolidinyl.
  • R 1 in a compound described herein may be a lipophilic moiety.
  • alkyl straight-chain and branched-chain monovalent substituents, as well as combinations of these, containing only C and H when unsubstituted.
  • alkyl group includes at least one carbon-carbon double bond or carbon-carbon triple bond, the alkyl group can be referred to as an "alkenyl” or “alkynyl” group respectively.
  • alkenyl or alkynyl group respectively.
  • the monovalency of an alkyl, alkenyl, or alkynyl group does not include the optional substituents on the alkyl, alkenyl, or alkynyl group.
  • alkyl, alkenyl, or alkynyl group is attached to a compound
  • monovalency of the alkyl, alkenyl, or alkynyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl, alkenyl, or alkynyl group.
  • the alkyl or heteroalkyl group may contain, e.g.,
  • the alkenyl, heteroalkenyl, alkynyl, or heteroalkynyl group may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10,
  • 2- 8, 2-6, or 2-4 carbon atoms e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2- C6, or C2-C4
  • Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2-propenyl, and 3-butynyl.
  • cycloalkyl represents a monovalent saturated or unsaturated non- aromatic cyclic alkyl group.
  • a cycloalkyl may have, e.g., three to twenty carbons (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C1 1 , C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkyl).
  • cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • the cycloalkyl group includes at least one carbon-carbon double bond, the cycloalkyl group can be referred to as a "cycloalkenyl" group.
  • a cycloalkenyl may have, e.g., four to twenty carbons (e.g., a C4-C7, C4-C8, C4-C9, C4-C10, C4-C1 1 , C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenyl).
  • Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • the cycloalkyl group includes at least one carbon-carbon triple bond, the cycloalkyl group can be referred to as a "cycloalkynyl" group.
  • a cycloalkynyl may have, e.g., eight to twenty carbons (e.g., a C8-C9, C8-C10, C8-C1 1 , C8-C12, C8-C14, C8-C16, C8-C18, or C8-C20 cycloalkynyl).
  • the term "cycloalkyl” also includes a cyclic compound having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.1 .]heptyl and adamantane.
  • cycloalkyl also includes bicyclic, tricyclic, and tetracyclic fused ring structures, e.g., decalin and spiro cyclic compounds.
  • aryl refers to any monocyclic or fused ring bicyclic or tricyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system, e.g., phenyl, naphthyl, or phenanthrene.
  • a ring system contains 5-15 ring member atoms or 5-10 ring member atoms.
  • An aryl group may have, e.g., five to fifteen carbons (e.g., a C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5-C1 1 , C5-C12, C5-C13, C5-C14, or C5-C15 aryl).
  • heteroaryl also refers to such monocyclic or fused bicyclic ring systems containing one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms selected from O, S and N.
  • a heteroaryl group may have, e.g., one to fifteen carbons (e.g., a C1 -C3, C1 -C4, C1 -C5, C1 -C6, C1 -C7, C1 -C8, C1 -C9.
  • heteroaryl systems include, e.g., pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzoisoxazolyl, and imidazolyl.
  • a group such as phthalimido is also considered heteroaryl.
  • the aryl or heteroaryl group is a 5- or 6-membered aromatic rings system optionally containing 1 -2 nitrogen atoms.
  • the aryl or heteroaryl group is an optionally substituted phenyl, pyridyl, indolyl, pyrimidyl, pyridazinyl, benzothiazolyl, benzimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, or imidazopyridinyl.
  • the aryl group is phenyl.
  • an aryl group may be optionally substituted with a substituent such an aryl substituent, e.g., biphenyl.
  • alkaryl refers to an aryl group that is connected to an alkylene, alkenylene, or alkynylene group. In general, if a compound is attached to an alkaryl group, the alkylene, alkenylene, or alkynylene portion of the alkaryl is attached to the compound.
  • an alkaryl is C6-C35 alkaryl (e.g., C6-C16, C6-C14, C6-C12, C6-C10, C6-C9, C6-C8, C7, or C6 alkaryl), in which the number of carbons indicates the total number of carbons in both the aryl portion and the alkylene, alkenylene, or alkynylene portion of the alkaryl.
  • alkaryls include, but are not limited to, (C1 -C8)alkylene(C6-C12)aryl, (C2-C8)alkenylene(C6-C12)aryl, or (C2-C8)alkynylene(C6-C12)aryl.
  • an alkaryl is benzyl.
  • one or more heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the alkaryl group and/or may be present in the aryl portion of the alkaryl group.
  • the substituent may be present on the alkylene, alkenylene, or alkynylene portion of the alkaryl group and/or may be present on the aryl portion of the alkaryl group.
  • amino represents -N(R X )2 or -N + (R X )3, where each R x is, independently, H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x combine to form a heterocycloalkyl.
  • the amino group is -NH2.
  • alkamino refers to an amino group, described herein, that is attached to an alkylene (e.g., C1 -C5 alkylene), alkenylene (e.g., C2-C5 alkenylene), or alkynylene group (e.g., C2-C5 alkenylene).
  • alkylene e.g., C1 -C5 alkylene
  • alkenylene e.g., C2-C5 alkenylene
  • alkynylene group e.g., C2-C5 alkenylene
  • the amino portion of an alkamino refers to -N(R X )2 or -N + (R X )3, where each R x is, independently, H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x combine to form a heterocycloalkyl.
  • the amino portion of an alkamino is -NH2.
  • An example of an alkamino group is C1 -C5 alkamino, e.g., C2 alkamino (e.g., CH2CH2NH2 or CH2CH2N(CH3)2).
  • heteroalkamino group one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the heteroalkamino group.
  • an alkamino group may be optionally substituted.
  • the substituent may be present on the alkylene, alkenylene, or alkynylene portion of the alkamino group and/or may be present on the amino portion of the alkamino group.
  • alkamide refers to an amide group that is attached to an alkylene (e.g., C1 -C5 alkylene), alkenylene (e.g., C2-C5 alkenylene), or alkynylene (e.g., C2-C5 alkenylene) group.
  • alkylene e.g., C1 -C5 alkylene
  • alkenylene e.g., C2-C5 alkenylene
  • alkynylene e.g., C2-C5 alkenylene
  • the amide portion of an alkamide refers to -C(0)-N(R X )2, where each R x is, independently, H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x combine to form a heterocycloalkyl.
  • the amide portion of an alkamide is -C(0)NH 2 .
  • An alkamide group may be -(CH 2 ) 2 -C(0)NH 2 or -CH 2 -C(0)NH 2 .
  • heteroalkamide group one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the heteroalkamide group.
  • an alkamide group may be optionally substituted.
  • the substituent may be present on the alkylene, alkenylene, or alkynylene portion of the alkamide group and/or may be present on the amide portion of the alkamide group.
  • alkylene refers to divalent groups having a specified size.
  • an alkylene may contain, e.g., 1 -20, 1 -18, 1 -16, 1 -14, 1 -12, 1 -10, 1 -8, 1 -6, 1 -4, or 1 -2 carbon atoms (e.g., C1 -C20, C1 -C18, C1 -C1 6, C1 -C14, C1 -C12, C1 -C10, C1 -C8, C1 -C6, C1 -C4, or C1 -C2).
  • an alkenylene or alkynylene may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4).
  • Alkylene, alkenylene, and/or alkynylene includes straight-chain and branched-chain forms, as well as combinations of these. The divalency of an alkylene, alkenylene, or alkynylene group does not include the optional substituents on the alkylene, alkenylene, or alkynylene group.
  • a ⁇ -1 ,3-glucan synthase inhibitor and a monosaccharide or oligosaccharide moiety may be attached to each other by way of a linker that includes alkylene, alkenylene, and/or alkynylene, or combinations thereof.
  • a linker that includes alkylene, alkenylene, and/or alkynylene, or combinations thereof.
  • Each of the alkylene, alkenylene, and/or alkynylene groups in the linker is considered divalent with respect to the two attachments on either end of alkylene, alkenylene, and/or alkynylene group.
  • a linker includes -(optionally substituted alkylene)-(optionally substituted alkenylene)-(optionally substituted alkylene)-
  • the alkenylene is considered divalent with respect to its attachments to the two alkylenes at the ends of the linker.
  • the optional substituents on the alkenylene are not included in the divalency of the alkenylene.
  • the divalent nature of an alkylene, alkenylene, or alkynylene group refers to both of the ends of the group and does not include optional substituents that may be present in an alkylene, alkenylene, or alkynylene group.
  • Alkylene, alkenylene, and/or alkynylene groups can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein.
  • -HCR-C ⁇ C- may be considered as an optionally substituted alkynylene and is considered a divalent group even though it has an optional substituent, R.
  • Heteroalkylene, heteroalkenylene, and/or heteroalkynylene groups refer to alkylene, alkenylene, and/or alkynylene groups including one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms, e.g., N, O, and S.
  • a polyethylene glycol (PEG) polymer or a PEG unit -(CH2)2-0- in a PEG polymer is considered a heteroalkylene containing one or more oxygen atoms.
  • cycloalkylene refers to a divalent cyclic group linking together two parts of a compound. For example, one carbon within the cycloalkylene group may be linked to one part of the compound, while another carbon within the cycloalkylene group may be linked to another part of the compound.
  • a cycloalkylene group may include saturated or unsaturated non-aromatic cyclic groups.
  • a cycloalkylene may have, e.g., three to twenty carbons in the cyclic portion of the cycloalkylene (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C1 1 , C3-C12, C3-C14, C3-C16, C3-C1 8, or C3-C20 cycloalkylene).
  • the cycloalkylene group includes at least one carbon-carbon double bond
  • the cycloalkylene group can be referred to as a "cycloalkenylene" group.
  • a cycloalkenylene may have, e.g., four to twenty carbons in the cyclic portion of the cycloalkenylene (e.g., a C4-C7, C4-C8, C4-C9. C4-C10, C4-C1 1 , C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenylene).
  • the cycloalkylene group includes at least one carbon-carbon triple bond
  • the cycloalkylene group can be referred to as a "cycloalkynylene" group.
  • a cycloalkynylene may have, e.g., four to twenty carbons in the cyclic portion of the cycloalkynylene (e.g., a C4-C7, C4-C8, C4-C9, C4-C10, C4-C1 1 , C4-C12, C4-C14, C4-C16, C4-C1 8, or C8-C20 cycloalkynylene).
  • a cycloalkylene group can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein.
  • Heterocycloalkylene refers to a cycloalkylene group including one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms, e.g., N, O, and S.
  • Examples of cycloalkylenes include, but are not limited to, cyclopropylene and cyclobutylene.
  • a tetrahydrofuran may be considered as a
  • arylene refers to a multivalent (e.g., divalent or trivalent) aryl group linking together multiple (e.g., two or three) parts of a compound. For example, one carbon within the arylene group may be linked to one part of the compound, while another carbon within the arylene group may be linked to another part of the compound.
  • An arylene may have, e.g., five to fifteen carbons in the aryl portion of the arylene (e.g., a C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5- C1 1 , C5-C12, C5-C13, C5-C14, or C5-C15 arylene).
  • An arylene group can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein.
  • Heteroarylene refers to an aromatic group including one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms, e.g., N, O, and S.
  • a heteroarylene group may have, e.g., two to fifteen carbons (e.g., a C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C10, C2-C1 1 , C2-C12, C2-C13, C2-C14, or C1 -C15 heteroarylene).
  • substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, alkaryl, acyl, heteroaryl, heteroalkyi, heteroalkenyl, heteroalkynyl, heteroalkaryl, halogen, oxo, cyano, nitro, amino, alkamino, hydroxy, alkoxy, alkanoyl, carbonyl, carbamoyl, guanidinyl, ureido, amidinyl, any of the groups or moieties described above, and hetero versions of any of the groups or moieties described above.
  • Substituents include, but are not limited to, F, CI, methyl, phenyl, benzyl, OR, NR 2 , SR, SOR, SO2R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOCR, SO3R, CONR2, SO2NR2, NRSO2NR2, CN, CF 3 , OCF 3 , S1R3, and NO2, wherein each R is, independently, H, alkyl, alkenyl, aryl, heteroalkyi, heteroalkenyl, or heteroaryl, and wherein two of the optional substituents on the same or adjacent atoms can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members, or two of the optional substituents on the same atom can be joined to form an optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members
  • an optionally substituted group or moiety refers to a group or moiety (e.g., any one of the groups or moieties described above) in which one of the atoms (e.g., a hydrogen atom) is optionally replaced with another substituent.
  • an optionally substituted alkyl may be an optionally substituted methyl, in which a hydrogen atom of the methyl group is replaced by, e.g., OH.
  • a substituent on a heteroalkyi or its divalent counterpart, heteroalkylene may replace a hydrogen on a carbon or a hydrogen on a heteroatom such as N.
  • the hydrogen atom in the group -R-NH-R- may be substituted with an alkamide substituent, e.g., -R- N[(CH2C(0)N(CH3)2]-R.
  • an optional substituent is a noninterfering substituent.
  • noninterfering substituent refers to a substituent that leaves the ability of the compounds described herein (e.g., compounds of any one of formulas (l)-(lll)) to bind to ⁇ -1 ,3-glucan synthase and/or to kill or inhibit the growth of fungi qualitatively intact. Thus, in some embodiments, the substituent may alter the degree of such activity.
  • a noninterfering substituent leaves the ability of a compound described herein (e.g., a compound of any one of formulas (l)-(lll)) to kill or inhibit the growth of fungi qualitatively intact as determined by measuring the minimum inhibitory concentration (MIC) against at least one fungi as known in the art.
  • MIC minimum inhibitory concentration
  • hetero when used to describe a chemical group or moiety, refers to having at least one heteroatom that is not a carbon or a hydrogen, e.g., N, O, and S. Any one of the groups or moieties described above may be referred to as hetero if it contains at least one heteroatom.
  • a heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl group refers to a cycloalkyl, cycloalkenyl, or cycloalkynyl group that has one or more heteroatoms, wherein each heteroatom is, independently, selected from, e.g., N, O, and S.
  • heterocycloalkenyl group is a maleimido.
  • a heteroaryl group refers to an aromatic group that has one or more heteroatoms, wherein each heteroatom is, independently, selected from, e.g., N, O, and S.
  • One or more heteroatoms may also be included in a substituent that replaced a hydrogen atom in a group or moiety as described herein.
  • a substituent e.g., methyl
  • the substituent may also contain one or more heteroatoms (e.g., methanol).
  • acyl refers to a group having the structure: wherein R z is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyi, cycloalkenyl, cycloalkynyl, aryl, alkaryl, alkamino, heteroalkyi, heteroalkenyl, heteroalkynyl, heterocycloalkyi, heterocycloalkenyl, heterocycloalkynyl, heteroaryl, heteroalkaryl, or heteroalkamino.
  • halo refers to any halogen atom, e.g., F, CI, Br, or I. Any one of the groups or moieties described herein may be referred to as a "halo moiety" if it contains at least one halogen atom, such as haloalkyl.
  • hydroxyl represents an -OH group.
  • carbonyl refers to a group having the structure
  • thiocarbonyl refers to a group having the structure
  • phosphate represents the group having the structure:
  • phosphoryl represents the group having the structure:
  • amino represents the group having the structure:
  • R is an optional substituent
  • V-protecting group represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N- protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 5th Edition (John Wiley & Sons, New York, 2014), which is incorporated herein by reference.
  • /V-protecting groups include, e.g., acyl, aryloyl, and carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, carboxybenzyl (CBz), 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acid residues such as alanine, leucine, phenylalanine; sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl; carb
  • amino acid means naturally occurring amino acids and non- naturally occurring amino acids.
  • Naturally occurring amino acids means amino acids including Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val.
  • non-naturally occurring amino acid means an alpha amino acid that is not naturally produced or found in a mammal.
  • non-naturally occurring amino acids include D-amino acids; an amino acid having an acetylaminomethyl group attached to a sulfur atom of a cysteine; a pegylated amino acid; the omega amino acids of the formula NH2(CH2) n COOH where n is 2-6, neutral nonpolar amino acids, such as sarcosine, t-butyl alanine, t-butyl glycine, N- methyl isoleucine, and norleucine; oxymethionine; phenylglycine; citrulline; methionine sulfoxide; cysteic acid; ornithine; diaminobutyric acid; 3-aminoalanine; 3-hydroxy-D-proline; 2,4-diaminobutyric acid; 2-aminopentanoic
  • amino acids are a-aminobutyric acid, ⁇ -amino-a-methylbutyrate, aminocyclopropane-carboxylate, aminoisobutyric acid, aminonorbornyl-carboxylate, L-cyclohexylalanine, cyclopentylalanine, L-N-methylleucine, L-N-methylmethionine, L-N-methylnorvaline, L-N-methylphenylalanine, L-N-methylproline,
  • L-N-methylserine L-N-methyltryptophan, D-ornithine, L-N-methylethylglycine, L-norleucine, a-methyl- aminoisobutyrate, a-methylcyclohexylalanine, D-a-methylalanine, D-a-methylarginine,
  • D-a-methylasparagine D-a-methylaspartate, D-a-methylcysteine, D-a-methylglutamine,
  • D-a-methylhistidine D-a-methylisoleucine, D-a-methylleucine, D-a-methyllysine,
  • D-a-methylmethionine D-a-methylornithine, D-a-methylphenylalanine, D-a-methylproline,
  • D-a-methylserine D-N-methylserine, D-a-methylthreonine, D-a-methyltryptophan, D-a-methyltyrosine, D-a-methylvaline, D-N-methylalanine, D-N-methylarginine, D-N-methylasparagine,
  • D-N-methylaspartate D-N-methylcysteine, D-N-methylglutamine, D-N-methylglutamate,
  • D-N-methylhistidine D-N-methylisoleucine, D-N-methylleucine, D-N-methyllysine, N-methylcyclohexylalanine, D-N-methylornithine, N-methylglycine, N-methylaminoisobutyrate, N-(1 -methylpropyl)glycine, N-(2-methylpropyl)glycine, D-N-methyltryptophan, D-N-methyltyrosine, D-N-methylvaline, ⁇ -aminobutyric acid, L-t-butylglycine, L-ethylglycine, L-homophenylalanine, L-a-methylarginine, L-a-methylaspartate, L-a-methylcysteine, L-a-methylglutamine,
  • L-a-methylhistidine L-a-methylisoleucine, L-a-methylleucine, L-a-methylmethionine,
  • L-a-methylnorvaline L-a-methylphenylalanine, L-a-methylserine, L-a-methyltryptophan,
  • L-a-methylvaline N-(N-(2,2-diphenylethyl) carbamylmethylglycine, 1 -carboxy-1 -(2,2-diphenyl- ethylamino) cyclopropane, 4-hydroxyproline, ornithine, 2-aminobenzoyl (anthraniloyl),
  • L-N-methylglutamine L-N-methylglutamic acid, L-N-methylhistidine, L-N-methylisoleucine,
  • L-N-methyllysine L-N-methylnorleucine, L-N-methylornithine, L-N-methylthreonine,
  • N-(2-methylthioethyl)glycine L-a-methyllysine, L-a-methylnorleucine, L-a-methylornithine,
  • L-a-methylproline L-a-methylthreonine, L-a-methyltyrosine, L-N-methyl-homophenylalanine,
  • amino acid residues may be charged or polar.
  • Charged amino acids include alanine, lysine, aspartic acid, or glutamic acid, or non-naturally occurring analogs thereof.
  • Polar amino acids include glutamine, asparagine, histidine, serine, threonine, tyrosine, methionine, or tryptophan, or non-naturally occurring analogs thereof.
  • a terminal amino group in the amino acid may be an amido group or a carbamate group.
  • fungal infection refers to the invasion of a subject's cells, tissues, and/or organs by fungi (e.g., Candida spp. or Aspergillus spp.), thus, causing an infection.
  • the fungi may grow, multiply, and/or produce toxins in the subject's cells, tissues, and/or organs.
  • a fungal infection can be any situation in which the presence of a fungal population(s) is latent within or damaging to a host body.
  • a subject is "suffering" from a fungal infection when a latent fungal population is detectable in or on the subject's body, an excessive amount of a fungal population is present in or on the subject's body, or when the presence of a fungal population(s) is damaging the cells, tissues, and/or organs of the subject.
  • the term "dermatophytosis” or “dermatophyte infection” refers to an infection caused by dermatophytes, which are fungi that require keratin for growth. Dermatophytes are fungi in the genus Microsporum, Epidermophyton, and Trichophyton. These fungi can cause superficial infections of the skin, hair, and/or nails. Dermatophytes are spread by direct contact from other people (anthropophilic organisms), animals (zoophilic organisms), and soil (geophilic organisms), as well as indirectly from fomites.
  • protecting against a fungal infection refers to preventing a subject from developing a fungal infection or decreasing the risk that a subject may develop a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.).
  • Prophylactic drugs used in methods of protecting against a fungal infection in a subject are often administered to the subject prior to any detection of the fungal infection.
  • a subject e.g., a subject at risk of developing a fungal infection
  • a compound described herein e.g., a compound having any one of formulas (l)-(lll)
  • treating refers to a therapeutic treatment of a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.) in a subject.
  • a therapeutic treatment may slow the progression of the fungal infection, improve the subject's outcome, and/or eliminate the infection.
  • a therapeutic treatment of a fungal infection e.g., a fungal infection caused by Candida spp.
  • a subject in a subject may alleviate or ameliorate of one or more symptoms or conditions associated with the fungal infection, diminish the extent of the fungal infection, stabilize (i.e., not worsening) the state of the fungal infection, prevent the spread of the fungal infection, and/or delay or slow the progress of the fungal infection, as compare the state and/or the condition of the fungal infection in the absence of therapeutic treatment.
  • the term "immunocompromised” refers to a subject (e.g., a human) having a weakened immune system.
  • the subject's immune system can be weakened or compromised by a disease (e.g., an HIV infection, an autoimmune disease, cancer), a medical procedure (e.g., an organ transplant (e.g., a solid organ transplant) or a bone marrow transplant), a drug (e.g., an HIV infection, an autoimmune disease, cancer), a medical procedure (e.g., an organ transplant (e.g., a solid organ transplant) or a bone marrow transplant), a drug (e.g., an HIV infection, an autoimmune disease, cancer), a medical procedure (e.g., an organ transplant (e.g., a solid organ transplant) or a bone marrow transplant), a drug (e.g., an HIV infection, an autoimmune disease, cancer), a medical procedure (e.g., an organ transplant (e.g., a solid
  • the immune system of the host may also have a congenital defect that renders the host more susceptible to infection.
  • an immunosuppression therapy refers to a therapy that uses one or more immunosuppressants to reduce the activation and/or efficacy of the immune system of a subject (e.g., a human).
  • an immunosuppression therapy is used to prevent the body from rejecting a transplant (e.g., an organ transplant (e.g., a solid organ transplant) or a bone marrow transplant), to treat graft-versus-host disease after a bone marrow transplant, and/or to treat autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, multiple sclerosis, myasthenia gravis, Sarcoidosis, Behcet's disease).
  • autoimmune diseases e.g., systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, multiple sclerosis, myasthenia gravis, Sarcoidosis, Behcet's disease
  • Immunosuppressants include, but are not limited to, calcineurin inhibitors, mTOR inhibitors, and tyrosine kinase inhibitors (e.g., cyclosporine A, cyclosporine G, voclosporin, tacrolimus, pimecrolimus, sirolimus, temsirolimus, deforolimus, everolimus, zotarolimus, biolimus, imatinib, dasatinib, nilotinib, erlotinib, sunitinib, gefitinib, bosutinib, neratinib, axitinib, crizotinib, lapatinib, toceranib and vatalanib).
  • calcineurin inhibitors e.g., cyclosporine A, cyclosporine G, voclosporin, tacrolimus, pimecrolimus, sirolimus, temsirolimus,
  • activating an immune cell refers to the ability of a compound to directly or indirectly bind to an immune cell to produce an effective immune response.
  • the ability of a compound to directly or indirectly bind to an immune cell to produce an effective immune response may be quantified by measuring the concentration of the compound at which such immune response is produced.
  • the concentration of a compound that binds to an immune cell receptor such as dectin-1 or binds to an antibody (e.g., anti-aGal or anti-aRha antibody, which then binds to an immune cell) to trigger an effective immune response may be less than or equal to 10,000 nM as measured in accordance with, e.g., an enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • an aGal epitope, that binds to an antibody, such as an anti-aGal antibody may be detected using an ELISA.
  • oligosaccharide moiety may be immobilized on a support or surface using conventional techniques in the art. After the compound is immobilized to the surface, an antibody that is specific for the particular monosaccharide or oligosaccharide moiety in the compound is applied over the surface so it is captured by the compound through binding to the monosaccharide or oligosaccharide moiety in the compound.
  • the antibody is often linked to an enzyme (e.g., horseradish peroxidase) for subsequent signal amplification.
  • the enzyme's substrate e.g., 3,3'-diaminobenzidine
  • the antibody itself can be detected using a secondary antibody, which is linked to an enzyme.
  • the concentration of a compound that binds to an immune cell receptor such as dectin-1 or binds to an antibody (e.g., anti-aGal or anti-aRha antibody, which then binds to an immune cell) to trigger an effective immune response may be less than or equal to 1000 nM or less than or equal to 100 nM as measured in accordance with an ELISA.
  • innate immune receptor refers to a natural receptor, such as a natural receptor on an immune cell, that binds to a carbohydrate (e.g., a monosaccharide or oligosaccharide moiety) or an optionally substituted carbohydrate and causes a response in the immune system.
  • an innate immune receptor binds to the monosaccharide or oligosaccharide moiety of the compounds described herein (e.g., compounds of any one of formulas (l)-(lll)).
  • an innate immune receptor binds to a moiety in Table 2A or 2B.
  • natural antibody refers to a naturally existing antibody in the circulation of a mammal (e.g., a human) that has not been previously exposed to deliberate immunization.
  • a natural antibody is an antibody of the immunoglobulin M (IgM) isotype.
  • IgM immunoglobulin M
  • a natural antibody binds to the monosaccharide or
  • a natural antibody binds to a moiety in Table 2A or 2B.
  • a natural antibody is anti-aGal antibobody or anti-aRha antibody.
  • subject can be a human, non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, turkey, goat, fish, monkey, chicken, rat, mouse, and sheep.
  • terapéuticaally effective amount refers to an amount, e.g., pharmaceutical dose, effective in inducing a desired effect in a subject or in treating a subject having a condition or disorder described herein (e.g., a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.)). It is also to be understood herein that a “therapeutically effective amount” may be interpreted as an amount giving a desired therapeutic and/or preventative effect, taken in one or more doses or in any dosage or route.
  • an effective amount of a compound is, for example, an amount sufficient to prevent, slow down, or reverse the progression of the fungal infection as compared to the response obtained without administration of the compound.
  • composition refers to a medicinal or
  • compositions that contains at least one active ingredient (e.g., a compound of any one of formulas (l)-(lll)) as well as one or more excipients and diluents to enable the active ingredient suitable for the method of administration.
  • active ingredient e.g., a compound of any one of formulas (l)-(lll)
  • excipients and diluents to enable the active ingredient suitable for the method of administration.
  • the pharmaceutical composition of the present disclosure includes pharmaceutically acceptable components that are compatible with a compound described herein (e.g., a compound of any one of formulas (l)-(lll)).
  • a pharmaceutically acceptable carrier refers to an excipient or diluent in a pharmaceutical composition.
  • a pharmaceutically acceptable carrier may be a vehicle capable of suspending or dissolving the active compound (e.g., a compound of any one of formulas (l)-(lll)).
  • the pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient.
  • the pharmaceutically acceptable carrier must provide adequate pharmaceutical stability to a compound described herein.
  • the nature of the carrier differs with the mode of administration. For example, for oral administration, a solid carrier is preferred; for intravenous administration, an aqueous solution carrier (e.g., WFI, and/or a buffered solution) is generally used.
  • pharmaceutically acceptable salt represents salts of the compounds described herein (e.g., compounds of any one of formulas (l)-(lll)) that are, within the scope of sound medical judgment, suitable for use in methods described herein without undue toxicity, irritation, and/or allergic response.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Pharmaceutical Salts:
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.
  • FIGS. 1 A and 1 B are fluorescent images showing the binding of the secondary anti-rabbit lgG1 (red fluorescence) to rabbit anti-Rha antibodies, which in turn are bound to A. fumigatus hyphae treated with Compound 1 (FIG. 1 A) or CD101 acetate (FIG. 1 B).
  • FIGs. 2A and 2B are graphs, and corresponding tables, showing Compound 1 concentrations as measured in frozen plasma collected from mice treated with 3 mg/kg or 10 mg/kg Compound 1 IV (Fig. 2A) or mice treated with 3 mg/kg or 10 mg/kg Compound 1 IP (Fig. 2B).
  • FIGs. 3A and 3B are graphs, and corresponding tables, showing Compound 1 concentrations as measured in lung homogenates prepared from mice treated with 3 mg/kg or 10 mg/kg Compound 1 IV (Fig. 3A) or mice treated with 3 mg/kg or 10 mg/kg Compound 1 IP (Fig. 3B).
  • FIGs. 4A and 4B are tables summarzing Compound 1 concentrations as measured in lung homogenates or plasma isolated from mice treated with 3 mg/kg or 10 mg/kg Compound 1 IV (Fig. 4A) or mice treated with 3 mg/kg or 10 mg/kg Compound 1 IP (Fig. 4B).
  • the disclosure features compounds, compositions, and methods for the treatment of fungal infections (e.g., fungal infections caused by Candida spp. or Aspergillus spp.J.
  • fungal infections e.g., fungal infections caused by Candida spp. or Aspergillus spp.J.
  • the inventors have found that compounds disclosed herein have increased antifungal activity due to their ability to bind to the fungal cell wall through inhibition of ⁇ -1 ,3-glucan synthase, thereby driving a concentration gradient near the locus of infection.
  • the compounds disclosed herein include a ⁇ -1 ,3-glucan synthase inhibitor covalently conjugated to a monosaccharide or oligosaccharide moiety by way of a linker.
  • the compounds disclosed herein include a ⁇ -1 ,3-glucan synthase inhibitor covalently conjugated to at least one monosaccharide or oligosaccharide moiety by way of a linker, ⁇ -1 ,3-glucan synthase is a glucosyltransferase enzyme involved in the generation of ⁇ -glucan in the cell wall of fungi. Inhibition of this enzyme results in disrupting the integrity of the fungal cell well and serves as a pharmacological target for antifungal drugs.
  • the monosaccharide or oligosaccharide moiety in the compounds described herein serve as a gradient against which immune cells chemotax to the site of fungal infection and/or growth.
  • ⁇ -1 ,3-glucan synthase inhibitor may be synthesized using available chemical synthesis techniques in the art.
  • available functional groups in the ⁇ -1 ,3-glucan synthase inhibitor, the linker, and the monosaccharide or oligosaccharide moiety e.g., amines, carboxylic acids, and/or hydroxyl groups, may be used in making the compounds described herein.
  • the nitrogen atom in an amine group of the ⁇ -1 ,3-glucan synthase inhibitor may form an amide bond with the carbon in a carboxylic acid group of the linker.
  • a molecule may be derivatized using conventional chemical synthesis techniques that are well known in the art.
  • the compounds described herein contain one or more chiral centers.
  • the compounds include each of the isolated stereoisomeric forms as well as mixtures of stereoisomers in varying degrees of chiral purity, including racemic mixtures. It also encompasses the various diastereomers, enantiomers, and tautomers that can be formed.
  • R 1 is a lipophilic moiety
  • R 2 is hydrogen or methyl
  • each of R 3 and R 4 is, independently, hydrogen or hydroxyl
  • R 5 is hydrogen, methyl, or optionally substituted C1-C5 alkamino
  • R 6 is hydrogen, hydroxyl, methyl, or amino
  • R 7 is hydrogen or hydroxyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(O(CH2)a)bR’, -(NH(CH2)a)bR’, -(S(CH2)a)bR’, -(O(CH2)a)bN(R’)2, -(NH(CH2)a)bN(R’)2, -(S(CH2)a)bN(R’)2, -(O(CH2)a)bN + (R’)3, -(NH(CH2)a)bN + (R’)3, -(S(CH2)a)bN + (R’)3, -(S(CH2)
  • R 9 is hydrogen, hydroxyl, or amino; n is 0 or 1; d is 1, 2, 3, 4, 5, or 6; each of a and b is, independently, an integer from 1 to 5; each R’ is, independently, hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-10 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl
  • the disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (1-1 ):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , n, d, L, and E are as described above.
  • the disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (I-2):
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH 2 (CO)NH 2
  • R 6 is hydrogen or methyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH2) a )bR',
  • each of a and b is, independently, an integer from 1 to 5; d is 1 , 2, 3, 4, 5, or 6; each R’ is, independently, hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-10 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1-C10 heteroaryl; L is a linker; and each
  • R 8 is -(O(CH2)a)bR’, -(NH(CH2)a)bR’, -(S(CH2)a)bR’, -(O(CH2)a)bN(R’)2, -(NH(CH2)a)bN(R’)2, -(S(CH2)a)bN(R’)2, -(O(CH2)a)bOR’, -(NH(CH2)a)bOR’,
  • R 8 is -OCH2CH2N(R’)2, -NHCH2CH2N(R’)2, -(NHCH2CH2)2N(R’)2, -NHCH2CH2OR’, -(NHCH2CH2)2OR’, -OCH2CH2NHCH2CH2N(R’)2,
  • R 1 is a lipophilic moiety
  • R 2 is hydrogen or methyl
  • each of R 3 and R 4 is, independently, hydrogen or hydroxyl
  • R 6 is hydrogen, hydroxyl, methyl, or amino
  • R 7 is hydrogen or hydroxyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(O(CH 2 ) a ) b R’, -(NH(CH 2 ) a ) b R’,
  • R 9 is hydrogen, hydroxyl, or amino; n is 0 or 1 ; each of a and b is, independently, an integer from 1 to 5; d is 1 , 2, 3, 4, 5, or 6; each R' is, independently, hydrogen, optionally substituted C1 -C10 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyl, optionally substituted C3
  • the disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (11-1 ):
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , n, d, L, and E are as defined above.
  • the disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (II-2):
  • R 1 is a lipophilic moiety
  • R 6 is hydrogen or methyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(O(CH2)a)bR’, -(NH(CH2)a)bR’, -(S(CH2)a)bR’, -(O(CH2)a)bN(R’)2, -(NH(CH2)a)bN(R’’)2, -(S(CH2)a)bN(R’)2, -(O(CH2)a)bN + (R’)3, -(NH(CH2)a)bN + (R’)3, -(S(CH2)a)bN + (R’)3, -(O(CH2)a)bOR’, -(NH(CH2)a)bOR’, -(S(CH2)a)bOR’, -(OCH2CH2)a(NHCH2CH2)
  • each of a and b is, independently, an integer from 1 to 5; d is 1, 2, 3, 4, 5, or 6; each R’ is, independently, hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-10 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C
  • R 8 is -(O(CH2)a)bR’, -(NH(CH2)a)bR’, -(S(CH2)a)bR’, -(O(CH2)a)bN(R’)2, -(NH(CH2)a)bN(R’’)2, -(S(CH2)a)bN(R’)2, -(O(CH2)a)bOR’, -(NH(CH2)a)bOR’,
  • each R’ is, independently, hydrogen or optionally substituted C1-C5 alkyl; and each R’’ is, independently, hydrogen, or C1-C10 alkyl, or a
  • R 8 is -OCH2CH2N(R’)2,
  • each R’ is, independently, hydrogen or methyl; each R’’ is,
  • R 8 is
  • R 8 is -(O(CH2)a)bN + (R’)3, -(NH(CH2)a)bN + (R’)3, -(S(CH2)a)bN + (R’)3,
  • R 8 is -OCH2CH2N + (R’)3, -(OCH2CH2)2N + (R’)3, -NHCH2CH2N + (R’)3, or -(NHCH2CH2)2N + (R’)3; each R’ is, independently, hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
  • R 8 is
  • R’ is
  • each R A is, independently, hydrogen or optionally substituted C1-C10 alkyl.
  • the disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (III):
  • R 1 is a lipophilic moiety
  • R 2 is hydrogen or methyl
  • each of R 3 and R 4 is, independently, hydrogen or hydroxyl
  • R 5 is hydrogen, methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen, hydroxyl, methyl, or amino
  • R 7 is hydrogen or hydroxyl
  • R 9 is hydrogen, hydroxyl, or amino
  • X is O or NH
  • n is 0 or 1
  • d is 1 , 2, 3, 4, 5, or 6
  • L is a linker
  • each E is, independently, a monosaccharide or oligosaccharide moiety.
  • the disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (III-1 ):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , X, n, d, L, and E are as defined above.
  • the disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (111-2):
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH 2 (CO)NH 2
  • R 6 is hydrogen or methyl
  • X is O or NH
  • d is 1 , 2, 3, 4, 5, or 6
  • L is a linker
  • each E is, independently, a monosaccharide or oligosaccharide moiety.
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • R 1 is a lipophilic moiety
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • d is 1, 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • R 1 is each of X and Y is, independently, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene, or is absent;
  • Z is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl
  • X, Y, and Z together, form wherein R B is an optionally substituted C1-C10 alkyl, or a pharmaceutically acceptable salt thereof.
  • X, Y, and Z together, form wherein R B is optionally substituted C1- C10 alkyl, or a pharmaceutically acceptable salt thereof.
  • R B is optionally substituted C1- C10 alkyl, or a pharmaceutically acceptable salt thereof.
  • R B is optionally substituted C1-C8 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 5 is methyl, -CH2CH2NH2, or -CH 2 (CO)NH 2 ;
  • R 6 is hydrogen or methyl;
  • R B is optionally substituted C1 -C6 alkyl;
  • d is 1 , 2, 3, or 4;
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • R 6 is hydrogen or methyl; R B is optionally substituted C1 -C6 alkyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the disclosure also provides a compound of any one of the following formulas:
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the portion in a compound described herein indicates that one or more (e.g., 1 , 2, 3, 4; 5, or 6; 1 -2, 1 -3, 1 -4, 1 -5, or 1 -6) monosaccharide or oligosaccharide moieties may be attached to L at any atom(s) within L.
  • E represents a monosaccharide or oligosaccharide moiety.
  • the portion is not to be construed as a single bond between one or more monosaccharide or oligosaccharide moieties and an atom in L. In some embodiments, when d is 1 , one monosaccharide or oligosaccharide moiety may be attached to an atom in L.
  • a linker in a compound described herein may be a branched structure.
  • a linker in a compound described herein may be a multivalent structure, e.g., divalent, trivalent, tetravalent, pentavalent, hexavalent, or heptavalent structure, containing two, three, four, five, six, or seven arms, respectively.
  • one arm may be attached to a ⁇ -1 ,3-glucan synthase inhibitor and the remaining arm(s) (e.g., the remaining one, two, three, four, five, or six arms) may each be attached to a monosaccaride or oligosaccharide moiety.
  • L in the portion may have multiple arms attached to multiple monosaccharide or oligosaccharide moieties.
  • ⁇ -1 ,3-glucan synthase inhibitors that can be functionalized to covalently conjugate to at least one monosaccharide or oligosaccharide moiety by way of a linker are shown below.
  • the disclosure also features a compound selected from
  • the pharmaceutically acceptable salt of any one of Compounds 1 -3, 4a, 4b, 5a-5c, and 6 is a formate salt. In some embodiments, the pharmaceutically acceptable salt of any one of Compounds 1 -3, 4a, 4b, 5a-5c, and 6 is an acetate salt.
  • the compound is Compound 1 ,
  • the pharmaceutically acceptable salt of Compound 1 is a formate salt. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is an acetate salt. In some embodiments, the compound is Compound 4a
  • the pharmaceutically acceptable salt of Compound 4a is a formate salt. In some embodiments, the pharmaceutically acceptable salt of Compound 4a is an acetate salt.
  • a linker refers to a linkage or connection between two or more components in a compound (e.g., between the ⁇ -1 ,3-glucan synthase inhibitor and the monosaccharide or oligosaccharide moiety in a compound described herein (e.g., a compound of any one of formulas (l)-(lll)).
  • a linker in a compound described herein e.g., L
  • L may be a branched structure.
  • a linker in a compound described herein may be a multivalent structure, e.g., divalent, trivalent, tetravalent, pentavalent, hexavalent, or heptavalent structure, containing two, three, four, five, six, or seven arms, respectively, in which each arm is covalently conjugated to either a ⁇ -1 ,3-glucan synthase inhibitor or a monosaccharide or oligosaccharide moiety.
  • a divalent linker L in the compound of any one of formulas (l)-(lll) is described by formula (L-l):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor
  • I 2 is a bond attached to a monosaccharide or oligosaccharide moiety (E);
  • each of U 1 , U 2 , U 3 , and U 4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20
  • R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl ; and each of f, g, h, i, j, k, I, m, and n is, independently,
  • a divalent linker is described by formula (L-11 ):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor
  • I 2 is a bond attached to a monosaccharide or oligosaccharide moiety (E);
  • a divalent linker is described by formula (L-I2), (L-I3), or (L-I4):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor
  • I 2 is a bond attached to a monosaccharide or oligosaccharide moiety (E);
  • a divalent linker is
  • a trivalent linker L in the compound of any one of formulas (I)-(III) is described by formula (L-II):
  • L A is described by formula G A1 -(Z A1 ) g1 -(Y A1 ) h1 -(Z A2 ) i1 -(Y A2 ) j1 -(Z A3 ) k1 -(Y A3 ) l1 -(Z A4 ) m1 -(Y A4 ) n1 - (Z A5 )o1-G A2 ;
  • L B is described by formula G B1 -(Z B1 )g2-(Y B1 )h2-(Z B2 )i2-(Y B2 )j2-(Z B3 )k2-(Y B3 )l2-(Z B4 )m2-(Y B4 )n2- (Z B5 )o2-G B2 ;
  • L C is described by formula G C1 -(Z C1 )g3-(Y C1 )h3-(Z C2 )i3-(Y C2 )j3-(Z
  • R i is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3- C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl ; and each of g1 , hi , i1 , j1 , k1 , 11 , ml ,
  • each of Y A1 , Y A2 , Y A3 , Y M , Y B1 , Y B2 , Y B3 , Y B4 , Y C1 , Y C2 , Y C3 , and Y C4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C1 5 arylene, or optionally substituted C1 -C15 heteroarylene; each of Z A1 , Z A2 , Y A3 , Y M , Y B1
  • a trivalent linker is
  • each of p, q, r, s, and t is, independently, an integer from 1 to 10.
  • a trivalent linker is
  • each of p, q, r, s, t, and u is, independently, an integer from 1 to 10.
  • a linker in a compound described herein may also have a tetravalent, pentavalent, hexavalent, or heptavalent structure, containing four, five, six, or seven arms, respectively.
  • the linker has four or more (e.g., five, six, or seven) arms, one arm may be attached to a ⁇ -1 ,3-glucan synthase inhibitor and the remaining arms (e.g., remaining three, four, or five arms) may each be attached to a monosaccharide or oligosaccharide moiety.
  • a linker L in the compound of any one of formulas (I)-(III) is described by formula (L-III):
  • L A is described by formula G A1 -(Z A1 ) g1 -(Y A1 ) h1 -(Z A2 ) i1 -(Y A2 ) j1 -(Z A3 ) k1 -(Y A3 ) l1 -(Z A4 ) m1 -(Y A4 ) n1 - (Z A5 )o1-G A2 ;
  • L B is described by formula G B1 -(Z B1 )g2-(Y B1 )h2-(Z B2 )i2-(Y B2 )j2-(Z B3 )k2-(Y B3 )l2-(Z B4 )m2-(Y B4 )n2- (Z B5 )o2-G B2 ;
  • L C is described by formula G C1 -(Z C1 )g3-(Y C1 )h3-(Z C2 )i3-(Y C2 )j3-(Z
  • each of Y A1 , Y A2 , Y A3 , Y A4 , Y B1 , Y B2 , Y B3 , Y B4 , Y C1 , Y C2 , Y C3 , Y C4 , Y D1 , Y D2 , Y D3 , Y D4 , Y E1 , Y E2 , Y E3 , Y E4 , Y F1 , Y F2 , Y F3 , Y F4 , Y G1 , Y G2 , Y G3 , and Y G4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20
  • heteroalkylene optionally substituted C2-C20 alkenylene, optionally substituted C2-C20
  • a multivalent linker in a compound described herein is
  • each of p, q, r, s, t, u, v, w, x, y, and z is, independently, an integer from 1 to 10.
  • a multivalent linker in a compound described herein is
  • each of p, q, r, s, and t is, independently, an integer from 1 to 10.
  • a linker L in the compound of any one of formulas (I)-(III) is described by formula (L-IV):
  • L A is described by formula G A1 -(Z A1 )g1-(Y A1 )h1-(Z A2 )i1-(Y A2 )j1-(Z A3 )k1-(Y A3 )l1-(Z A4 )m1-(Y A4 )n1- (Z A5 )o1-G A2 ;
  • L B is described by formula G B1 -(Z B1 )g2-(Y B1 )h2-(Z B2 )i2-(Y B2 )j2-(Z B3 )k2-(Y B3 )l2-(Z B4 )m2-(Y B4 )n2- (Z B5 )o2-G B2 ;
  • L C is described by formula G C1 -(Z C1 )g3-(Y C1 )h3-(Z C2 )i3-(Y C2 )j3-(Z C3 )k3-(Y C3 )l3-
  • a multivalent linker in a compound described herein is
  • each of p, q, r, s, and t is, independently, an integer from 1 to 10.
  • a linker provides space, rigidity, and/or flexibility between the ⁇ -1 ,3- glucan synthase inhibitor and the monosaccharide or oligosaccharide moiety.
  • a linker may be a bond, e.g., a covalent bond, e.g., an amide bond, a disulfide bond, a C-N bond, a N- N bond, or any kind of bond created from a chemical reaction, e.g., chemical conjugation.
  • a linker includes no more than 250 atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1- 16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-110, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1- 240, or 1-250 atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 atom(s)).
  • a linker includes no more than 250 non- hydrogen atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1- 45, 1 -50, 1 -55, 1 -60, 1 -65, 1 -70, 1 -75, 1 -80, 1 -85, 1 -90, 1 -95, 1 -100, 1-110, 1-120, 1 -130, 1 -140, 1 - 150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1-240, or 1-250 non-hydrogen atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26,
  • the backbone of a linker includes no more than 250 atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1-45, 1-50, 1-55, 1- 60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-110, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1-240, or 1-250 atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 atom(s)).
  • the "backbone" of a linker refers to the atoms in the linker that together form the shortest path from one part of the compound to another part of the compound.
  • the atoms in the backbone of the linker are directly involved in linking one part of the compound to another part of the compound.
  • hydrogen atoms attached to carbons in the backbone of the linker are not considered as directly involved in linking one part of the compound to another part of the compound.
  • a divalent linker may contain two carboxylic acids, in which the first carboxylic acid may form a covalent linkage with one component (e.g., a ⁇ -1 ,3-glucan synthase inhibitor) in the compound and the second carboxylic acid may form a covalent linkage with another component (e.g., a monosaccharide or oligosaccharide moiety) in the compound.
  • one component e.g., a ⁇ -1 ,3-glucan synthase inhibitor
  • another component e.g., a monosaccharide or oligosaccharide moiety
  • one end of the linker may form a covalent linkage with the ⁇ -1 ,3-glucan synthase inhibitor in the compound and the other end of the linker may form a covalent linkage (e.g., a C-0 bond, a C-S bond, or a C-N bond) with the monosaccharide or oligosaccharide moiety.
  • a covalent linkage e.g., a C-0 bond, a C-S bond, or a C-N bond
  • dicarboxylic acid molecules may be used as linkers (e.g., a dicarboxylic acid linker).
  • linkers e.g., a dicarboxylic acid linker
  • the first carboxylic acid in a dicarboxylic acid molecule may form a covalent linkage with the ⁇ -1 ,3-glucan synthase inhibitor and the second carboxylic acid may form a covalent linkage with the monosaccharide or oligosaccharide moiety.
  • dicarboxylic acids molecules that may be used to serve as linkers in compounds disclosed herein (e.g., compounds of formulas (l)-(lll)) include, but are not limited to,
  • dicarboxylic acid molecules such as the ones described herein, may be further functionalized to contain one or more additional functional groups, which may be used to conjugate to one or more monosaccharide or oligosaccharide moieties.
  • a molecule containing one or more sulfonic acid groups may be used to form a linker, in which the sulfonic acid group may form a sulfonamide linkage with a nitrogen in a ⁇ -1 ,3-glucan synthase inhibitor .
  • a molecule containing one or more isocyanate groups may be used to form a linker, in which the isocyanate group may form a urea linkage with a nitrogen in a ⁇ -1 ,3-glucan synthase inhibitor.
  • a molecule containing one or more haloalkyl groups may be used to form a linker, in which the haloalkyl group may form a covalent linkage, e.g., C-N and C-0 linkages, with a ⁇ -1 ,3-glucan synthase inhibitor.
  • a linker may include a synthetic group derived from, e.g., a synthetic polymer (e.g., a polyethylene glycol (PEG) polymer).
  • a linker may include one or more amino acid residues.
  • a linker may be an amino acid sequence (e.g., a 1 -25 amino acid, 1 -10 amino acid, 1 -9 amino acid, 1 -8 amino acid, 1 -7 amino acid, 1 -6 amino acid, 1 -5 amino acid, 1 -4 amino acid, 1 -3 amino acid, or 1 -2 amino acid sequence).
  • a linker may include one or more optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene (e.g., a PEG unit), optionally substituted C2-C20 alkenylene (e.g., C2 alkenylene), optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene (e.g., cyclopropylene, cyclobutylene), optionally substituted C3-C20
  • heterocycloalkylene optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene (e.g., C6 arylene), optionally substituted C1 -C15 heteroarylene (e.g., imidazole, pyridine), O, S, NR' (R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocyclo
  • L in a compound of any one of formulas (l)-(lll) may have a formula of (L-l), (L-ll), (L-lll), or (L-IV).
  • Covalent conjugation of two or more components in a compound using a linker may be accomplished using well-known organic chemical synthesis techniques and methods.
  • Complementary functional groups on two components may react with each other to form a covalent bond.
  • Examples of complementary reactive functional groups include, but are not limited to, e.g., amine and activated carboxylic acid, thiol and maleimide, activated sulfonic acid and amine, isocyanate and amine, azide and alkyne, and alkene and tetrazine.
  • Other examples of functional groups capable of reacting with amino groups include, e.g., alkylating and acylating agents.
  • amino-reactive acylating groups include, e.g., (i) an isocyanate and an isothiocyanate; (ii) a sulfonyl chloride; (iii) an acid halide; (iv) an active ester, e.g., a nitrophenylester or N-hydroxysuccinimidyl ester; (v) an acid anhydride, e.g., a mixed, symmetrical, or N- carboxyanhydride; (vi) an acylazide; and (vii) an imidoester. Aldehydes and ketones may be reacted with amines to form Schiff's bases, which may be stabilized through reductive amination.
  • a monosaccharide moiety is a molecular moiety that has one optionally substituted C6-C9 (exclusive of the substituents) monosaccharide residue.
  • An oligosaccharide moiety is a molecular moiety that includes at least two, e.g., 2-150 (e.g., 2-149, 2-140, 2-130, 2-120, 2-1 10, 2-100, 2-90,
  • an oligosaccharide moiety includes 2-18 optionally substituted C6-C9 (exclusive of the substituents) monosaccharide residues. In some embodiments, an oligosaccharide moiety includes 2-12 optionally substituted C6-C9 (exclusive of the substituents) monosaccharide residues.
  • an oligosaccharide moiety has a molecule weight that does not exceed 30 kDa, 25 kDa, 24 kDa, 23 kDa, 22 kDa, 21 kDa, 20 kDa, 19 kDa, 18 kDa, 17 kDa, 16 kDa, 1 5 kDa, 14 kDa, 13 kDa, 12 kDa, 1 1 kDa, 10 kDa, 9 kDa, 8 kDa, 7 kDa, 6 kDa, 5 kDa or 3 kDa.
  • a monosaccharide moiety has an optionally substituted C6-C9 monosaccharide residue selected from glucose (Glc), galactose (Gal), mannose (Man), allose (All), altrose (Alt), gulose (Gul), idose (Ido), talose (Tal), fucose (Fuc), rhamnose (Rha; also called
  • a monosaccharide moiety has an optionally substituted C6-C9 monosaccharide residue selected from Rha, Gal, Glc, GlcA (Glucuronic acid), GlcNAc, GalNAc, GlcN(Gc) (N-Glycolyl-Glucosamine), Neu5Ac, Neu5Gc (N-Glycolyl-neuraminic acid), Fuc, Man, -htePOsMan (mannose phosphate), 6-H2PO3GIC (glucose phosphate), Mur (muramoyl), Mur-L-Ala-D-i- Gln-Lys, (Mur)-3-0-GlcNAc, sulfate-galactose (Su-Gal), disulfate-galactose (Su2-Gal), sulfate-glucose (Su-Glc), sulfate-GlcNAc (Su-Glc
  • Rhamnose occurs in nature in its L-form, thus, rhamnose is also referred to as
  • L-rhamnose or L-Rha may be in a form (also called a-Rha or a-L-Rha) or ⁇ form (also called ⁇ -Rha or ⁇ -L-Rha).
  • Thia-rhamnose has -SH attached at the anomeric carbon instead of -OH.
  • Thia-rhamnose is also referred to as thia-Rha or thia-L-Rha.
  • Thia-rhamnose may be in a form (also called thia-a-Rha or thia-a-L-Rha) or in ⁇ form (also called thia ⁇ -Rha or thia ⁇ -L-Rha).
  • the structures of Rha, a-Rha, and ⁇ -Rha are shown below.
  • the monosaccharide moiety is an optionally substituted a-Rha or an optionally substituted thia-a-Rha.
  • a compounds described herein may contain a-Rha.
  • each of the optionally substituted C6-C9 monosaccharide residues may, independently, joined to an adjacent monosaccharide residue through an O-glycosidic, S-glycosidic, N-glycosidic linkage, or C-glycosidic.
  • the binding at an O-glycosidic, S- glycosidic, N-glycosidic, or C-glycosidic linkage may be an a- or ⁇ -configuration, for example, through 1 ,2-, 1 ,3-, 1 ,4-, 1 ,6-, 2,3-, 2,6-, or 2,8-linkage, or a linkage such as 3-0, for example, a1 -2, a1 -3, a1 -4, ⁇ 1 -6, ⁇ 2-3, ⁇ 2-6, ⁇ 2-8, ⁇ 1 -2, ⁇ 1 -3, ⁇ 1 -4, or ⁇ 1 -6.
  • each of the optionally substituted C6-C9 monosaccharide residues is, independently, glucose (Glc), galactose (Gal), mannose (Man), allose (All), altrose (alt), gulose (Gul), idose (ido), talose (Tal), fucose (Fuc), rhamnose (Rha), quinovose (Qui), 2-deoxyglucose (2-dGlc), glucosamine (GlcN), galactosamine (GaIN), mannosamine (ManN), fucosamine (FucN), quinovosamine (QuiN), N-Acetyl-glucosamine (GlcNAc); N-Acetyl-galactosamine (GalNAc), N-Acetyl-mannosamine (ManNAc), N-acetyl-fucosamine (FucNAc), N-acetyl-quinovosamine (QuiNAc
  • each of the optionally substituted C6-C9 monosaccharide residues is, independently, Rha, Gal, Glc, GlcA (Glucuronic acid), GlcNAc, GalNAc, GlcN(Gc) (N-Glycolyl-Glucosamine), Neu5Ac, Neu5Gc (N-Glycolyl-neuraminic acid), Fuc, Man, -FtePCbMan (mannose phosphate), 6-H2PO3GIC (glucose phosphate), Mur
  • an oligosaccharide moiety may be straight or branched.
  • the optionally substituted monosaccharide residue(s) i.e., at least one monosaccharide residue
  • the optionally substituted monosaccharide residue(s) is substituted with one or more, such as 1 -3, substituents independently selected from sulfate, phosphate, methyl, acetyl, naturally amino acids, and non-naturally occurring amino acids.
  • the optionally substituted monosaccharide residue(s) i.e., at least one monosaccharide residue
  • the optionally substituted monosaccharide residue(s) is substituted with one or more, such as 1 -3, substituents, wherein each substituent is, independently, selected from sulfate, phosphate, methyl, acetyl.
  • the optionally substituted monosaccharide residue(s) i.e., at least one monosaccharide residue
  • the monosaccharide residue or oligosaccharide moiety is substituted with one or more, such as 1 -3, substituents, wherein each substituent is, independently, selected from naturally occurring amino acids and non-naturally occurring amino acids.
  • the linkage may be, for example, a a1 -0 linkage.
  • the linkage may be through a hydroxyl group, for example, a 2-0, 3-0 , 4-0, or 6-0 linkage, such as 3-0-Su-Gal, (6-0-Su)Gal, (6-0-Su)Glc, 6-0-Su-GlcNAc, (6-0- Su)GalNAc, 3,6-0-Su2-Gal, 3,4-0-Su2-Gal, or 4-0-Su-Gal.
  • a 2-0, 3-0 , 4-0, or 6-0 linkage such as 3-0-Su-Gal, (6-0-Su)Gal, (6-0-Su)Glc, 6-0-Su-GlcNAc, (6-0- Su)GalNAc, 3,6-0-Su2-Gal, 3,4-0-Su2-Gal, or 4-0-Su-Gal.
  • Naturally occurring amino acids include Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, He, Leu,
  • a non-naturally occurring amino acid is an amino acid that is not naturally produced or found in a mammal.
  • non-naturally occurring amino acids include D-amino acids; an amino acid having an acetylaminomethyl group attached to a sulfur atom of a cysteine; a pegylated amino acid; the omega amino acids of the formula NH2(CH2)nCOOH where n is 2-6, neutral nonpolar amino acids, such as sarcosine, t-butyl alanine, t-butyl glycine, N- methyl isoleucine, and norleucine; oxymethionine; phenylglycine; citrulline; methionine sulfoxide; cysteic acid; ornithine; diaminobutyric acid; and hydroxyproline.
  • amino acids are a- aminobutyric acid, ⁇ -amino-a-methylbutyrate, aminocyclopropane-carboxylate, aminoisobutyric acid, aminonorbornyl-carboxylate, L-cyclohexylalanine, cyclopentylalanine, L-N-methylleucine,
  • L-N-methylmethionine L-N-methylnorvaline, L-N-methylphenylalanine, L-N-methylproline,
  • L-N-methylserine L-N-methyltryptophan, D-ornithine, L-N-methylethylglycine, L-norleucine, a-methyl- aminoisobutyrate, a-methylcyclohexylalanine, D-a-methylalanine, D-a-methylarginine,
  • D-a-methylasparagine D-a-methylaspartate, D-a-methylcysteine, D-a-methylglutamine,
  • D-a-methylhistidine D-a-methylisoleucine, D-a-methylleucine, D-a-methyllysine,
  • D-a-methylmethionine D-a-methylornithine, D-a-methylphenylalanine, D-a-methylproline,
  • D-a-methylserine D-N-methylserine, D-a-methylthreonine, D-a-methyltryptophan, D-a-methyltyrosine, D-a-methylvaline, D-N-methylalanine, D-N-methylarginine, D-N-methylasparagine,
  • D-N-methylaspartate D-N-methylcysteine, D-N-methylglutamine, D-N-methylglutamate,
  • D-N-methylhistidine D-N-methylisoleucine, D-N-methylleucine, D-N-methyllysine,
  • L-a-methylarginine L-a-methylaspartate, L-a-methylcysteine, L-a-methylglutamine,
  • L-a-methylhistidine L-a-methylisoleucine, L-a-methylleucine, L-a-methylmethionine,
  • L-a-methylnorvaline L-a-methylphenylalanine, L-a-methylserine, L-a-methyltryptophan,
  • L-a-methylvaline N-(N-(2,2-diphenylethyl) carbamylmethylglycine, 1 -carboxy-1 -(2,2-diphenyl- ethylamino) cyclopropane, 4-hydroxyproline, ornithine, 2-aminobenzoyl (anthraniloyl),
  • L-N-methylglutamine L-N-methylglutamic acid, L-N-methylhistidine, L-N-methylisoleucine,
  • L-N-methyllysine L-N-methylnorleucine, L-N-methylornithine, L-N-methylthreonine,
  • N-(3-indolylyethyl)glycine N-methyl-Y-aminobutyrate, D-N-methylmethionine,
  • N-(p-hydroxyphenyl)glycine N-(thiomethyl)glycine, penicillamine, L-a-methylalanine,
  • L-a-methylasparagine L-a-methyl-t-butylglycine, L-methylethylglycine, L-a-methylglutamate,
  • L-a-methylhomophenylalanine N-(2-methylthioethyl)glycine, L-a-methyllysine, L-a-methylnorleucine, L-a-methylornithine, L-a-methylproline, L-a-methylthreonine, L-a-methyltyrosine, L-N-methyl- homophenylalanine, N-(N-(3,3-diphenylpropyl) carbamylmethylglycine, L-pyroglutamic acid,
  • D-pyroglutamic acid O-methyl-L-serine, O-methyl-L-homoserine, 5-hydroxylysine,
  • amino acid residues may be charged or polar.
  • Charged amino acids include alanine, lysine, aspartic acid, or glutamic acid, or non-naturally occurring analogs thereof.
  • Polar amino acids include glutamine, asparagine, histidine, serine, threonine, tyrosine, methionine, or tryptophan, or non-naturally occurring analogs thereof.
  • non-natural amino acids that may be included in a compound described herein (e.g., a compound of any one of formulas (l)-(lll)), for example, in the linker portion of the compound, include, but are not limited to, D-Ser, D-Pro, D-Leu, D-Nle (D-norleucine), D-Thr, D-Val, L-Abu (L-2-aminobutyric acid), 3-(2H-tetrazol-5-yl)alanine, 3-aminoalanine, piperazine-2- carboxylic acid, 2,4-diaminobutyric acid, 3-hydroxyproline, 2-amino-4-phenylbutyric acid,
  • the optionally substituted monosaccharide residue(s) i.e., at least one monosaccharide residue
  • the optionally substituted monosaccharide residue(s) i.e., at least one monosaccharide residue in the monosaccharide or oligosaccharide moiety is an optionally substituted C6 monosaccharide residue.
  • the optionally substituted C6 monosaccharide residue is optionally substituted Gal or optionally substituted Glc.
  • the optionally substituted Gal is optionally substituted a1 -3Gal.
  • the optionally substituted Glc is an optionally substituted ⁇ -glucan having 1 -6 Glc moieties.
  • the optionally substituted monosaccharide residue(s) i.e., at least one monosaccharide residue
  • the optionally substituted monosaccharide residue(s) in the monosaccharide or oligosaccharide moiety is an optionally substituted C9 monosaccharide residue, e.g., sialic acid (Sia), Neuraminic acid (Neu), N-Acetyl- neuraminic acid (Neu5Ac), or N-Glycolyl-neuraminic acid (Neu5Gc).
  • the optionally substituted monosaccharide residue(s) may include a hexose residue, e.g., glucose (Glc), galactose (Gal), mannose (Man), allose (All), altrose (alt), gulose (Gul), idose (ido), or talose (Tal).
  • a hexose residue e.g., glucose (Glc), galactose (Gal), mannose (Man), allose (All), altrose (alt), gulose (Gul), idose (ido), or talose (Tal).
  • the optionally substituted monosaccharide residue(s) may include a deoxyhexose residue, e.g., a hexose residue without the hydroxyl group at the 6-position or the 2-position, e.g., fucose (Fuc), rhamnose (Rha), quinovose (Qui), or 2-deoxyglucose (2-dGlc).
  • a deoxyhexose residue e.g., a hexose residue without the hydroxyl group at the 6-position or the 2-position, e.g., fucose (Fuc), rhamnose (Rha), quinovose (Qui), or 2-deoxyglucose (2-dGlc).
  • the optionally substituted monosaccharide residue(s) may also include an aminohexose residue, e.g., a hexose residue with an amino group or an N-acetylated amino group at the 2 -position, e.g., glucosamine (GlcN), galactosamine (GaIN), mannosamine (ManN), fucosamine (FucN), quinovosamine (QuiN), N-Acetyl-glucosamine (GlcNAc), N-Acetyl-galactosamine (GalNAc), N-Acetyl-mannosamine (ManNAc), N-acetyl-fucosamine (FucNAc), or N-acetyl-quinovosamine (QuiNAc).
  • an aminohexose residue e.g., a hexose residue with an amino group or an N-acetylated amino group at the 2 -position
  • the optionally substituted monosaccharide residue(s) may include a uronic acid residue, e.g., a hexose residue with a negatively charged carboxylate at the 6-position, e.g., glucuronic acid (GlcA), galacturonic acid (GalA), mannuronic acid (ManA), or iduronic acid (IdoA).
  • a uronic acid residue e.g., a hexose residue with a negatively charged carboxylate at the 6-position
  • glucuronic acid GlcA
  • GalA galacturonic acid
  • ManA mannuronic acid
  • IdoA iduronic acid
  • the optionally substituted monosaccharide residue(s) may include a sialic acid residue, e.g., a residue of a nine-carbon acidic sugar, e.g., a residue of. Sialic acid (Sia), Neuraminic acid (Neu), N-Acetyl-neuraminic acid (Neu5Ac), or N-Glycolyl-neuraminic acid (Neu5Gc).
  • the optionally substituted monosaccharide residue(s) may include a sugar alcohol, e.g., glucitol (Glc-ol), galactitol (Gal-ol), or mannitol (Man-ol).
  • a sugar alcohol e.g., glucitol (Glc-ol), galactitol (Gal-ol), or mannitol (Man-ol).
  • the optionally substituted monosaccharide residue(s) may include other compounds, e.g., thevetose (The), acofriose (Aco), digitoxose (Dig), cymarose (Cym), abequose (Abe), colitose (Col), tyvelose (Tyv), ascarylose (Asc), paratose (Par), and N-acetyl-muramic acid (MurNAc).
  • the optionally substituted monosaccharide residue(s) i.e., at least one monosaccharide residue
  • the monosaccharide or oligosaccharide moiety is Gal, such as aGal (for example, a1 -3Gal).
  • An aGal epitope i.e., an oligosaccharide moiety that exhibits specific binding to an anti-aGal antibody, may also include a moiety including an a-D-galactopyranoside moiety, Gal, Galal-3Gal, Galal-4Gal, Galal-6Gal, Galal-3Gala1 -3GlcNAc, Galal-3Gala1 -4Gal, Galal-3Gala1 - 4GlcNAc, Galal-3Gala1 -4Glc, Galal-3Gala1 -4[3-deoxy]GlcNAc, Galal-3Gala1 -4[6-deoxy]GlcNAc, Galal-3Gala1 -4Gala1 -3Gal, Galal-3Gala1 -4GlcNAca1 -3Gala1 -4Glc, and any multimers and combinations thereof.
  • Galal-3Gal 1 -4GlcNAc-R (aGal
  • aGal epitopes that may be included in a compound described here (e.g., a compound of any one of formulas (l)-(lll)) are shown below:
  • optional substituents may include 1 -3 substituents, wherein each substituent is, independently, selected from sulfate, phosphate, methyl, acetyl, naturally occurring amino acid residues, and non-naturally occurring amino acid residues on each monosaccharide residue. These may be linked through an O, S, or N, such as a sulfamate linkage through an S.
  • the amino acid residues may be charged or polar and includes isomers thereof.
  • Charged amino acids include alanine, lysine, aspartic acid, or glutamic acid.
  • Polar amino acids include glutamine, asparagine, histidine, serine, threonine, tyrosine, methionine, or tryptophan.
  • the amino acid substituent if present, may be alanine, lysine, serine, glutamine, or i-glutamine, or asparagine.
  • the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety may contain at least one (such as 1 -12) of the following optionally substituted monosaccharide residues: Rha, Gal, Glc, GlcA (Glucuronic acid), GlcNAc, GalNAc, GlcN(Gc) (N-Glycolyl-Glucosamine), Neu5Ac, Neu5Gc
  • the 1 -12 optionally substituted C6-C9 monosaccharide residues in the monosaccharide or oligosaccharide moiety may be ⁇ -glucan residues.
  • the ⁇ -Glucan residue includes 2-12 optionally substituted glucopyranosyl monosaccharide residues, wherein each residue is, independently, joined to an adjacent glucopyranosyl monosaccharide residue via an O-glycosidic, S-glycosidic, N-glycosidic, or C-glycosidic linkage to form ⁇ -linked chains, which retain the ability to bind dectin-1 .
  • Optional substituents may include, e.g., 1 -3 substituents, such as with acetyl, sulfate, phosphate, or a natural or non-natural amino acid.
  • substituents include, e.g., 1 -3 substituents, such as with acetyl, sulfate, phosphate, or a natural or non-natural amino acid.
  • ⁇ -glucan residues include thia ⁇ -glucan residues such as the structures shown below:
  • an oligosaccharide moiety may be a ⁇ -glucan having more than 10 monosaccharides and/or a molecular weight of at least 3 kDa (e.g., 3-30 kDa; e.g., 3-29, 3-25, 3-20, 3-15, 3-10, 3-8, 3-6, 3-5, or 3-4 kDa).
  • an oligosaccharide moiety may be a ⁇ (1 ⁇ 3, 1 ⁇ 6)-glucan, e.g., laminarin, or a ⁇ (1 ⁇ 6)-glucan, e.g., pustulan.
  • a monosaccharide or oligosaccharide moiety directly or indirectly activates an immune cell.
  • the monosaccharide or oligosaccharide moiety directly binds an immune cell.
  • ⁇ -glucans bind dectin-1 receptors. When bound to dectin-1 , which internalizes the ⁇ -glucan, ⁇ -glucan mediates the production of reactive oxygen species (ROS), activation of NF- ⁇ , and subsequent secretion of proinflammatory cytokines.
  • ROS reactive oxygen species
  • the ⁇ - glucan receptor, dectin-1 is predominantly expressed on the surface of cells of
  • the monosaccharide or oligosaccharide moiety indirectly binds an immune cell.
  • the monosaccharide or oligosaccharide moiety may bind to an antibody.
  • the antibody in turn may bind to Fc receptors found on the surface of certain on immune cells including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, and mast cells.
  • aGal or aRha will bind to anti-aGal or anti-aRha antibody, respectively, thereby indirectly activating immune cells.
  • a monosaccharide or oligosaccharide moiety is a ligand to an innate immune receptor.
  • the innate immune receptor is AICL, BDCA2, CLEC2,
  • the monosaccharide or oligosaccharide moiety binds to an antibody.
  • the antibody is a natural antibody.
  • the natural antibody is an antibody of the immunoglobulin M (IgM) isotype. Glycans bound by antibodies contained in intravenous immunoglobulin (IVIG) are studied by Gunten et al., J. Allergy Clin Immunol.
  • a monosaccharide or oligosaccharide moiety in a compound described herein may be any one of the glycans listed in Tables I and E1 of Gunten et al. Examples of glycans studied by Gunten et al. are shown in Table 2A. Anti-carbohydrate antibodies found in normal sera have been studied by Huflejt et al., Molecular Immunology 46:3037-3049, 2009, using a library of glycans shown in Table 2B.
  • Gc glycolyl
  • GIcA glucuronic acid
  • Mur muramoyi
  • OS oligosaccharide
  • P phosphate
  • Ser. Sia Neu5Ac
  • Parameter that describe properties of immunoprofiles of carbohydrate-binding antibodies are median and median absolute deviation.
  • a low median indicates that most donors show low intensities of antibodies bound to the given glycan, while a large median suggests that there is a significant number of donors with large antibody binding intensities to the given glycan.
  • Any of the glycan moieties in Tables 2A and 2B may be used as the monosaccharide or oligosaccharide moiety herein, such as a glycan moiety with a relatively larger median.
  • a compounds described herein may contain one or more monosaccharide or oligosaccharide moieties having the structures shown below:
  • Methods of the invention include, e.g., methods of protecting against or treating a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.) in a subject and methods of stabilizing or inhibiting the growth of fungi, or killing fungi.
  • a method of treating a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.) in a subject includes administering to the subject a compound described herein (e.g., a compound of any one of formulas (l)-(lll)) or a pharmaceutical composition thereof.
  • a method of stabilizing or inhibiting the growth of fungi, or killing fungi includes contacting the fungi or a site susceptible to fungal growth with a compound described herein (e.g., a compound of any one of formulas (l)-(lll)) or a pharmaceutical composition thereof).
  • a compound described herein e.g., a compound of any one of formulas (l)-(lll)
  • a pharmaceutical composition thereof e.g., a compound of any one of formulas (l)-(lll)
  • a compound described herein e.g., a compound of any one of formulas (l)-(lll)
  • a pharmaceutical composition thereof may be administered to the subject intravenously, subcutaneously, topically, or orally.
  • a compound described herein e.g., a compound of any one of formulas (l)-(lll)
  • a pharmaceutical composition thereof is administered to treat a blood stream infection or tissue infection in the subject.
  • the subject may be immunocompromised, and thus, is at a higher risk for developing a fungal infection.
  • the subject is being prepared for an invasive medical procedure or undergoing long term antibiotic therapy.
  • the subject has been diagnosed with humoral immune deficiency, T cell deficiency, neutropenia, asplenia, or complement deficiency.
  • the subject is being treated or is about to be treated with immunosuppresive drugs.
  • the subject has been diagnosed with a disease which causes immunosuppression (e.g., cancer or acquired immunodeficiency syndrome).
  • the subject has cancer (e.g., leukemia, lymphoma, or multiple myeloma).
  • the subject has undergone or is about to undergo immunosuppression therapy. In some embodiments, the subject has undergone or is about to undergo hematopoietic stem cell transplantation. In some embodiments, the subject has undergone or is about to undergo an organ transplant.
  • the fungal infection is selected from candidemia, invasive candidiasis, tinea capitis, tinea corporis, tinea pedis, onychomycosis, perionychomycosis, pityriasis versicolor, oral thrush, vaginal candidiasis, respiratory tract candidiasis, biliary candidiasis, eosophageal candidiasis, urinary tract candidiasis, systemic candidiasis, mucocutaneous candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis, or chronic sinusitis.
  • the fungal infection is candidemia or invasive candidiasis.
  • the fungal infection is an infection of Candida albicans, C. glabrata, C. dubliniensis, C. krusei, C. parapsilosis, C. tropicalis, C.
  • orthopsilosis C. guilliermondii, C. rugosa, C. auris, C. lusitaniae, Aspergillus fumigatus, A. flavus, A. terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus.
  • the fungal infection is an infection of Fusarium spp., Scedosporium spp., Mucor spp., Rhizopus spp., Rizomucor spp., Cunninghamella spp., Apophysomyces spp., Absidia spp., Saksenaea spp., Acremonium spp., Paecilomyces spp., Trichoderma spp., Stachybotrys spp., Trichophyton spp., Microsporum spp., Epidermophyton spp., Sporothrix spp., Histoplasma spp., Coccidioides spp., Blastomyces spp., Paracoccidioides spp., the
  • the Fusarium spp. is F. solani, F. oxysporum, F. verticillioides, or F. moniliforme.
  • the Scedosporium spp. is S. apiospermum or S. prolificans.
  • ffte Mt/cor spp. is M circinelloides, M. azygosporus, or M. circinelloides.
  • the Rhizopus spp. is ft oryzae.
  • the Rizomucor spp. is ft pusillus.
  • the Cunninghamella spp. is £ bertholletiae.
  • the Apophysomyces spp. is /A. elegans. In some embodiments, the Absidia spp. is /A. corymbifera. In some embodiments, the Saksenaea spp. is S. vasiformis. In some embodiments, the Acremonium spp. is /A. strictum. In some embodiments, the Paecilomyces spp. is P. Iilacinus or P. variotii. In some embodiments, the Trichoderma spp. is ⁇ . longibrachiatum, T. harzianum, T. koningii, T.
  • the Stachybotrys spp. is S.
  • the Trichophyton spp. is ⁇ . rubrum, T. mentagrophytes, T.
  • the Microsporum spp. is M gypseum.
  • the Epidermophyton spp. is E. floccosum.
  • the Sporothrix spp. is S. schenckii.
  • the Histoplasma spp. is -/. capsulatum.
  • the Coccidioides spp. is £ immitis or £ posadasii. In some embodiments, the
  • Blastomyces spp. is B. dermatitidis.
  • the Paracoccidioides spp. is P.
  • the Cladosporium spp. is C trichoides.
  • the Exophiala spp. is E. jeanselmei.
  • the Exserohilum spp. is E. rostratum, E. longirostratum, or E. mcginnisii.
  • a compound described herein may be formulated in a pharmaceutical composition for use in the methods described herein.
  • a compound described herein may be formulated in a pharmaceutical composition.
  • the pharmaceutical composition includes a compound described herein (e.g., a compound described by any one of formulas (l)-(lll)) and pharmaceutically acceptable carriers and excipients.
  • Acceptable carriers and excipients in the pharmaceutical compositions are nontoxic to recipients at the dosages and concentrations employed.
  • Acceptable carriers and excipients may include buffers such as phosphate, citrate, HEPES, and TAE, antioxidants such as ascorbic acid and methionine, preservatives such as hexamethonium chloride, octadecyldimethylbenzyl ammonium chloride, resorcinol, and benzalkonium chloride, proteins such as human serum albumin, gelatin, dextran, and immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acid residues such as glycine, glutamine, histidine, and lysine, and carbohydrates such as glucose, mannose, sucrose, and sorbitol.
  • buffers such as phosphate, citrate, HEPES, and TAE
  • antioxidants such as ascorbic acid and methionine
  • preservatives such as hex
  • excipients examples include, but are not limited to, antiadherents, binders, coatings, compression aids, disintegrants, dyes, emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, sorbents, suspensing or dispersing agents, or sweeteners.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylit
  • the compounds herein may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds herein be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
  • Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulphuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like for forming basic salts. Methods for preparation of the appropriate salts are well-established in the art.
  • Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate
  • alkali or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium,
  • a compound herein or a pharmaceutical composition thereof used in the methods described herein will be formulated into suitable pharmaceutical compositions to permit facile delivery.
  • a compound e.g., a compound of any one of formulas (l)-(lll)
  • a pharmaceutical composition thereof may be formulated to be
  • intramuscularly intravenously (e.g., as a sterile solution and in a solvent system suitable for intravenous use), intradermal ⁇ , intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally,
  • intravaginally intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally (e.g., a tablet, capsule, caplet, gelcap, or syrup), topically (e.g., as a cream, gel, lotion, or ointment), locally, by inhalation, by injection, or by infusion (e.g., continuous infusion, localized perfusion bathing target cells directly, catheter, lavage, in cremes, or lipid compositions).
  • infusion e.g., continuous infusion, localized perfusion bathing target cells directly, catheter, lavage, in cremes, or lipid compositions.
  • a compound herein or a pharmaceutical composition thereof may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic delivery, or aerosols.
  • the compositions may be formulated according to conventional pharmaceutical practice.
  • a compound described herein may be formulated in a variety of ways that are known in the art.
  • a compound described herein can be formulated as pharmaceutical or veterinary compositions.
  • a compound described herein is formulated in ways consonant with these parameters.
  • a summary of such techniques is found in Remington: The Science and Practice of Pharmacy, 22nd Edition, Lippincott Williams & Wilkins (2012); and Encyclopedia of Pharmaceutical Technology, 4th Edition, J. Swarbrick and J. C. Boylan, Marcel Dekker, New York (2013), each of which is
  • Formulations may be prepared in a manner suitable for systemic administration or topical or local administration.
  • Systemic formulations include those designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration.
  • the formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, and preservatives.
  • the compounds can be administered also in liposomal compositions or as microemulsions.
  • Systemic administration may also include relatively noninvasive methods such as the use of suppositories, transdermal patches, transmucosal delivery and intranasal administration.
  • Oral administration is also suitable for compounds herein. Suitable forms include syrups, capsules, and tablets, as is understood in the art.
  • compositions can be administered parenterally in the form of an injectable formulation.
  • Pharmaceutical compositions for injection can be formulated using a sterile solution or any pharmaceutically acceptable liquid as a vehicle.
  • Formulations may be prepared as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions.
  • Pharmaceutically acceptable vehicles include, but are not limited to, sterile water, physiological saline, and cell culture media (e.g., Dulbecco's Modified Eagle Medium (DMEM), a-Modified Eagles Medium (a-MEM), F-12 medium).
  • DMEM Dulbecco's Modified Eagle Medium
  • a-MEM a-Modified Eagles Medium
  • injectable compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, such as sodium acetate and sorbitan monolaurate.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, such as sodium acetate and sorbitan monolaurate.
  • compositions can be prepared in the form of an oral formulation.
  • Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including
  • microcrystalline cellulose starches including potato starch, croscarmellose sodium, alginates, or alginic acid
  • binding agents e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol
  • lubricating agents, glidants, and antiadhesives e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc).
  • Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
  • compositions for oral formulations include, but are not limited to, colorants, flavoring agents, plasticizers, humectants, and buffering agents.
  • Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
  • Dissolution or diffusion controlled release of a compound described herein e.g., a compound of any one of formulas (l)-(lll)
  • a pharmaceutical composition thereof can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of the compound, or by incorporating the compound into an appropriate matrix.
  • a controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol
  • palmitostearate ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2- hydroxymethacrylate, methacrylate hydrogels, 1 ,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols.
  • the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax, and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.
  • the pharmaceutical composition may be formed in a unit dose form as needed.
  • the amount of active component, e.g., a compound described herein (e.g., a compound of any one of formulas (I)- (III)), included in the pharmaceutical compositions are such that a suitable dose within the designated range is provided (e.g., a dose within the range of 0.01 -100 mg/kg of body weight).
  • compounds herein may be administered by any appropriate route for treating or protecting against a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp), or for preventing, stabilizing, or inhibiting the growth of fungi, or killing fungi (e.g., Candida spp. or Aspergillus spp).
  • a fungal infection e.g., a fungal infection caused by Candida spp. or Aspergillus spp
  • Compounds described herein may be administered to humans, domestic pets, livestock, or other animals with a pharmaceutically acceptable diluent, carrier, or excipient.
  • administering includes administration of any of the compounds described herein (e.g., compounds of any one of formulas (l)-(lll)) or compositions intramuscularly, intravenously (e.g., as a sterile solution and in a solvent system suitable for intravenous use), intradermal ⁇ , intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally,
  • intravaginally intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally (e.g., a tablet, capsule, caplet, gelcap, or syrup), topically (e.g., as a cream, gel, lotion, or ointment), locally, by inhalation, by injection, or by infusion (e.g., continuous infusion, localized perfusion bathing target cells directly, catheter, lavage, in cremes, or lipid compositions).
  • infusion e.g., continuous infusion, localized perfusion bathing target cells directly, catheter, lavage, in cremes, or lipid compositions.
  • (l)-(lll)) or a pharmaceutical compositions thereof depends on factors including the route of administration, the disease to be treated (e.g., the extent and/or condition of the fungal infection), and physical characteristics, e.g., age, weight, general health, of the subject.
  • the amount of the compound or the pharmaceutical composition thereof contained within a single dose may be an amount that effectively prevents, delays, or treats the fungal infection without inducing significant toxicity.
  • a pharmaceutical composition may include a dosage of a compound described herein ranging from 0.01 to 500 mg/kg (e.g., 0.01 , 0.1 , 0.2, 0.3, 0.4, 0.5, 1 , 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg/kg) and, in a more specific
  • a compound described herein e.g., a compound of any one of formulas (l)-(lll)
  • a pharmaceutical composition thereof may be administered to a subject in need thereof, for example, one or more times (e.g., 1 -10 times or more; 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 times) daily, weekly, monthly, biannually, annually, or as medically necessary. Dosages may be provided in either a single or multiple dosage regimens. The timing between administrations may decrease as the medical condition improves or increase as the health of the patient declines. The dosage and frequency of administration may be adapted by the physician in accordance with conventional factors such as the extent of the infection and different parameters of the subject.
  • Analytical HPLC was performed using the following column and conditions: Atlantis T3, 3 micron, 3.0 x 75 mm ; 50°C, water/CH 3 CN + 0.1 % formic acid, 5 to 95% CH 3 CN over 1 1 min + 2 min hold.
  • Preparative HPLC was performed using the following column: Agilent ZORBAX SB-CN, 7 ⁇ , 21 .2 x 250 mm, CH3CN/H2O/0.1 % Acetic Acid various linear gradients as necessary at 20 mL/min.
  • Rapid LC A Waters BEH C18, 3.0 x 30 mm, 1 .7 ⁇ , was used at a temperature of 50 ° C and at a flow rate of 1 .5 mL/min, 2 ⁇ injection, mobile phase: (A) water with 0.1 % formic acid and 1 % acetonitrile, mobile phase (B) methanol with 0.1 % formic acid; retention time given in minutes.
  • Polar Stop-Gap An Agilent Zorbax Bonus RP, 2.1 x 50mm, 3.5 ⁇ , was used at a temperature of 50°C and at a flow rate of 0.8 mL/min, 2 ⁇ injection, mobile phase: (A) water with 0.1 % formic acid and 1 % acetonitrile, mobile phase (B) methanol with 0.1 % formic acid; retention time given in minutes.
  • NMR Spectra were acquired on either of two instruments: (1 ) Agilent (formerly Varian) Unitylnova 400 MHz NMR spectrometer equipped with a 5mm Automation Triple Broadband (ATB) probe. The ATB probe was simultaneously tuned to 1 H, 19F and 13C. (2) Agilent (formerly Varian) Unitylnova 500 MHz NMR spectrometer. Several NMR probes are available for use with the 500 MHz NMR spectrometer, including both 3 mm and 5 mm 1 H13C1 5N probes and a 3 mm X1 H19F NMR probe (usually X is tuned to 13C).
  • the pulse angle was 45 degrees, 8 scans were summed and the spectral width was 16 ppm (-2 ppm to 14 ppm).
  • a total of 32768 complex points were collected during the 5.1 second acquisition time, and the recycle delay was set to 1 second.
  • Spectra were collected at 25 S C.
  • 1 H NMR Spectra are typically processed with 0.3 Hz line broadening and zero-filling to 131072 points prior to Fourier transformation.
  • Step c Synthesis of benzyl (2-(2-(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)carbamate
  • Succinic anhydride (156 mg, 1 .57 mmol) was added to a stirring mixture of INT-1 (375 mg, 1 .49 mmol) and DIEA (193 mg, 1 .49 mmol) in MeOH (7 mL) and the reaction was stirred at RT for 3 hours at room temperature.
  • the solvent was reduced by 80% on the rotary evaporator and the mixture was applied to reversed phase HPLC (5 to 50% acetonitrile in Dl water containing 0.1 % formic acid: 20 minute gradient).
  • Step f Synthesis of 4-[(2- ⁇ 2-[(6-deoxy-alpha-L- mannopyranosyl)oxy]ethoxy ⁇ ethyl)amino]-4-oxobutanoic acid (INT-2)
  • Example 3 Synthesis of 2-aminoethyl 2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl-(1->3)- 2,4,6-tri-0-acetyl-3-thio-beta-D-glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-1 ,3-dithio-beta-D- glucopyranoside (INT-3)
  • Step a Synthesis of (3aR,5R,6R,6aR)-5-((R)-2,2-dimethyl-1 ,3-dioxolan-4-yl)-2,2- dimethyltetrahydro-2H-furo[2,3-d][1 ,3]dioxol-6-yl trifluoromethanesulfonate
  • Triflic anhydride (7.8 mL, 46.39 mmol) was added over 30 minutes to a cold (0°C) solution of the diacetone allofuranose (10.50 g, 40.34 mmol) in pyridine (100 mL). After stirring in the ice-bath for 1 hour, the reaction was diluted with ethyl acetate (250 mL) and the organic layer was washed with a mixture of saturated sodium bicarbonate and brine (50 mL + 50 mL), dried (Na2S04) and concentrated under reduced pressure to provide the crude triflate.
  • Step b Synthesis of Thio-linked Disaccharide: ((2R,3R,4S,5R,6S)-2-[(acetyloxy)methyl]- 6- ⁇ [(3aR,5R,6S,6aS)-5-(2,2-dimethyl-1 dioxolan-4-yl)-2,2-dimethyltetrahydro-2H-furo[2,3- d][1 ,3]dioxol-6-yl]sulfanyl ⁇ oxane-3,4,5-triyl triacetate)
  • the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (400 mL), washed with water (200 mL), dried (Na2S04), and concentrated. Added 40 mL of EtOH to the residue to dissolve the foam followed by swirling the flask. The foam slowly turn to white solid. After standing still for 5 minutes, breaking down the solid cake and filtering and washing with 20% aq. EtOH (100 mL). After drying, 1 0.28 g of the title compound was obtained (44%). Check TLC of the mother liquor and some of the product remained in the mother liquor which was purified with normal phase flash column.
  • Step c Synthesis of 1 ,2,4,6-tetra-0-acetyl-3-S-(2,3,4,6-tetra-0-acetyl-beta-D- glucopyranosyl)-3-thio-D-glucopyranose
  • Step e Synthesis of (1->3)-Thiodisaccharide Thiol: 2,4,6-tri-0-acetyl-3-S-(2,3,4,6-tetra- 0-acetyl-beta-D-glucopyranosyl)-1 ,3-dithio-beta-D-glucopyranose
  • Step f Synthesis of Thio-linked Trisaccharide: 2,4,6-tri-0-acetyl-3-S-(2,3,4,6-tetra-0- acetyl-beta-D-glucopyranosyl)-1 ,3-dithio-beta-D-glucopyranose
  • Chloroform-d ⁇ 170.53 (e), 170.48(e), 170.16(e), 169.42(e), 1 69.26(e), 169.09(e), 168.47(e),
  • Step g Synthesis of Peracetylated (1->3)-Thiotrisaccharide: 2,3,4,6-tetra-O-acetyl-beta- D-glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-3-thio-beta-D-glucopyranosyl-(1->3)-1 ,2,4,6-tetra-0- acetyl-3-thio-D-glucopyranose
  • Step h Synthesis of (1->3)-Thiotrisaccharide Bromide: 2,3,4,6-tetra-O-acetyl-beta-D- glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-3-thio-beta-D-glucopyranosyl-(1->3)-1 ,2,4,6-tetra-0- acetyl-3-thio-D-glucopyranose
  • Step i Synthesis of (1->3)-Thiotrisaccharide Thiol: 2,3,4,6-tetra-O-acetyl-beta-D- glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-3-thio-beta-D-glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl- 1 ,3-dithio-beta-D-glucopyranose
  • Step j Synthesis of Peracetylated (1->3)-Thiotrisaccharide ethyleneamine: 2- aminoethyl 2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-3-thio-beta-D- glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-1 ,3-dithio-beta-D-glucopyranoside (INT-3)
  • TMP Trimethylphosphine
  • ADDP 1 ,1 '-(azodicarbonyl)dipiperidine
  • N-Cbz-ethanolamine (0.201 g, 1 .03 mmol) and 2,3,4,6-tetra-O- acetyl-beta-D-glucopyranosyl-(1 ->3)-2,4,6-tri-0-acetyl-3-thio-beta-D-glucopyranosyl-(1 ->3)-2,4,6-tri-0- acetyl-1 ,3-dithio-beta-D-glucopyranose (0.54 mmol in 5 mL of THF) were added sequentially to the solution, with further stirring at room temperature for 2 hours. Any precipitate was then filtered off and the solution evaporated to dryness.
  • Part 2 (Hydrogenolysis).
  • the compound from Example 3, Step j, Part 1 (0.500 g, 0.435 mmol) and 30% Pd/C (0.463 g, 1 .30 mmol) were in the flask with 20 ml_ of EtOH and 5 ml_ of CHC . Under H2, the reaction mixture was stirred overnight.
  • Check TLC and mass. Celite filtration and wash with EtOH gave the title compound 0.44 g (100%). Mass showed a strong detectable positive charge signal at tr 3 min with 8 min (5 ⁇ 95%)/highMW method (found M+H + : 1016.2).
  • INT-3 (1 eq) is dissolved in methanol and excess NaOMe (10 eq) is added. The reaction is stirred until LCMS shows substantial formation of the desired product (INT-4) with an exact mass of 595.14.
  • Example 5 Synthesis of (1->3)-Thiotrisaccharide ethyleneamine: 4-[(2- ⁇ [beta-D- glucopyranosyl-(1->3)-3-thio-beta-D-glucopyranosyl-(1->3)-3-thio-beta-D- glucopyranosyl]thio ⁇ ethyl)amino]-4-oxobutanoic acid (INT-5)
  • Step a Succinic anhydride (0.0879 g, 0.869 mmol) was added to INT-3 (0.4417 g, 0.435 mmol) in DCM/Py (20 mL). The reaction mixture was stirred at room temperature overnight. LC/MS 8min Positive/negative showed the desired peak mass at 4.3 min on negative ionization. The solvent was removed and the residue was loaded onto an Isco Gold 24g column and eluted with 4- 6%MeOH/DCM to give 0.27 g of the desired product.
  • Step b NaOMe in MeOH (25%, 1 .42 mL, 25 equiv.) was added into a 50-mL RB Flask which contained the product of Step a (0.270 g, 0.242 mmol) in 5 mL of MeOH. The mixture was stirred at room temperature for 60 hours. It was then acidified with 1 N aq. HCI and purified with reversed phase C18 column (0-3% CAN/water) to give 0.168 g (99.8%) of the title compound (INT-5). LC/MS 8 min pos/neg method showed negative mass at the very beginning (M-H, 694.2).
  • Step a Synthesis of 1 ,2,3,4-tetra-0-acetyl-6-deoxy-6-iodo-beta-D-glucopyranose
  • Step b Synthesis of (1->6)-Thiodisaccharide: 1 ,2,3,4-tetra-0-acetyl-6-S-(2,3,4,6-tetra-0- acetyl-beta-D-glucopyranosyl)-6-thio-beta-D-glucopyranose
  • Step c Synthesis of (1->6)-Thiodisaccharide Bromide: 2,3,4-tri-0-acetyl-6-S-(2,3,4,6- tetra-O-acetyl-beta-D-g lucopyranosyl)-6-th io-alpha-D-g lucopyranosyl brom ide
  • Step d Synthesis of (1->6)-Thiodisaccharide Thiol: 2,3,4-tri-0-acetyl-6-S-(2,3,4,6-tetra- 0-acetyl-beta-D-glucopyranosyl)-1 ,6-dithio-beta-D-glucopyranose
  • Step g Synthesis of (1->6)-Thiotrisaccharide Thiol: 2,3,4,6-tetra-O-acetyl-beta-D- glucopyranosyl-(1->6)-2,3,4-tri-0-acetyl-6-thio-beta-D-glucopyranosyl-(1->6)-2,3,4-tri-0-acetyl- 1 ,6-dithio-beta-D-glucopyranose
  • Step h Synthesis of Peracetylated (1->6)-Trisaccharide ethyleneamine: 2-aminoethyl 2,3,4,6-tetra-O-acetyl-beta-D-g lucopyranosyl-(1 ->6)-2,3,4-tri-0-acetyl-6-th io-beta-D- glucopyranosyl-(1->6)-2,3,4-tri-0-acetyl-1 ,6-dithio-beta-D-glucopyranoside
  • INT-7 is obtained having an exact mass of 595.14.
  • Example 8 Synthesis of (1->6)-Thiotrisaccharide ethyleneamine: 4-[(2- ⁇ [beta-D- glucopyranosyl-(1->6)-6-thio-beta-D-glucopyranosyl-(1->6)-6-thio-beta-D- glucopyranosyl]thio ⁇ ethyl)amino]-4-oxobutanoic acid (INT-8)
  • Step a An analogous procedure was used as that for the preparation of the compound from Example 5, Step a.
  • the desired compound (0.480 g) was obtained in 99% yield.
  • Step b An analogous procedure was used as that for the preparation of the compound from Example 5, Step b. INT-8 (0.275 g, 99% yield) was obtained. Negative ion was found (M-H-: 694.0). 1 3 C NMR (75 MHz, D 2 0): ⁇ 180.94 (e), 175.76 (e), 87.07 (0), 86.04 (0), 85.34 (0), 79.74 (0), 79.23 (0), 79.20 (0), 77.14 (0), 76.87 (0, 2C), 72.70 (0), 72.46 (0), 72.41 (0, 2C), 72.33 (0), 69.37 (0), 60.77 (e), 39.43 (e), 33.07 (e), 32.94 (e), 32.30 (e), 32.01 (e), 29.51 (e).
  • Example 9 Synthesis of INT-9
  • Triethylamine (1 .31 mL, 9.32 mmol) was added to a cold (0°C) solution of 2-(2- aminoethoxy)ethan-1 -ol (CAS# 929-06-6, 1 .00 g, 9.32 mmol) in anhydrous THF (100 mL).
  • Cbz chloride (1 .50 mL, 10.3 mmol).
  • the reaction was diluted with ethyl acetate (250 mL) and the organic layer was washed with a mixture of saturated sodium bicarbonate and brine (50 mL + 50 mL), dried (Na2S04) and concentrated under reduced pressure to provide the crude product.
  • Step b Synthesis of Per-acetyl Rhamnose Bromide: 2,3,4-tri-0-acetyl-6-deoxy-beta-L- mannopyranosyl bromide
  • Step d Synthesis of Rhamnose-PEG1-NHCbz: benzyl (2- ⁇ 2-[(2,3,4-tri-0-acetyl-6-deoxy- alpha-L-mannopyranosyl)thio]ethoxy ⁇ ethyl)carbamate
  • TMP Trimethylphosphine
  • ADDP 1 ,1 '- (azodicarbonyl)dipiperidine
  • Step f Synthesis of Rhamnosyl-PEG1-Succinic acid linker: 4-[(2- ⁇ 2-[(6-deoxy-alpha-L- mannopyranosyl)thio]ethoxy ⁇ ethyl)amino]-4-oxobutanoic acid (INT-9)
  • anidulafungin is nitrated and the nitro group reduced to provide INT-1 1 with an exact mass of 1 154.52.
  • pneumocandin Bo is nitrated and the nitro group reduced to provide INT-12 with an exact mass of 1079.57.
  • HATU 122 mg, 0.32 mmol, in 1 ml_ DMF
  • INT-2 1 18 mg, 0.34 mmol
  • INT-10 190 mg, 0.15 mmol
  • DMF 2 ml_
  • the reaction was stirred for an additional 20 minutes then applied directly to reversed phase HPLC (10 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 25 minute gradient).
  • the pure fractions were pooled and lyophilized to afford the product as a white solid.
  • the compound (a bis-rhamnose adduct) was dissolved in methanol (15 mL) and sodium carbonate ( ⁇ 5 mg) was added and the mixture stirred for 30 minutes at which point LC/MS analysis showed complete hydrolysis of the bis-rhamnose adduct and formation of the desired mon-rhamnose adduct.
  • the mixture was filtered and neutralized with glacial acetic acid ( ⁇ 1 mL), then concentrated and applied directly to reversed phase HPLC (10 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 25 minute gradient). The pure fractions were pooled and lyophilized to afford the product
  • Compound 3 is prepared from INT- 12 and INT-2.
  • Compound 3 has an exact mass of 1412.72.
  • Step b Acylation of Fmoc-caspofungin with INT-2
  • Step b Compound 4b with an exact mass of 1425.79 is prepared starting with caspofungin and INT-2.
  • 3'-Amino-htyr-CD101 (INT-10) (1 .0 mmol, 1 .0 eq) and trimethylamine (1 .1 mmol, 1 .1 eq) is dissolved in DMF (1 0 mL) and succinic anhydride (1 .1 mmol, 1 .1 eq) is added followed by DMAP (0.05 eq). The mixture is stirred until the INT-10 is mostly consumed as determined by analytical HPLC. The fractions containing compound with an exact mass of 1340.63 are collected by preparative reversed phase HPLC and lyophilization of those fractions gives the desired product.
  • test organisms consisted of strains from the Micromyx collection. Reference isolates were originally received from the American Type Culture Collection (ATCC; Manassas, VA).
  • Organisms received at Micromyx were initially streaked for isolation on Sabouraud dextrose or potato dextrose agar. Colonies were picked by swab from the medium and resuspended in the appropriate broth containing cryoprotectant. The suspensions were aliquoted into cryogenic vials and maintained at -80 S C. Prior to testing, Candida isolates were streaked from the frozen vials on Sabouraud dextrose agar. The yeast isolates were incubated at overnight at 35 S C before use. The fungal isolates were incubated at least 7 days on Sabouraud dextrose agar slants at 35 S C before harvesting. Test Media
  • Isolates were tested in RPMI medium (Catalog No. SH3001 1 .04; Lot No. AWA92121 B;
  • HyClone Labs, Logan, UT which was prepared according to CLSI guidelines.
  • the pH of the medium was adjusted to 7.0 with 1 N NaOH.
  • the medium was sterile filtered using a 0.2 ⁇ PES filter and stored at 4°C until used.
  • the MIC assay method employed automated liquid handlers to conduct serial dilutions and liquid transfers.
  • Automated liquid handlers included the Multidrop 384 (Labsystems, Helsinki, Finland), Biomek 2000 and Biomek FX (Beckman Coulter, Fullerton CA).
  • the wells in columns 2-12 in standard 96-well microdilution plates (Costar 3795) were filled with 150 ⁇ of the correct diluent
  • the daughter plates were loaded with 185 ⁇ per well of RPMI described above using the Multidrop 384.
  • the daughter plates were prepared using the Biomek FX which transferred 5 ⁇ of drug solution from each well of a mother plate to the corresponding well of the daughter plate in a single step.
  • a standardized inoculum of each organism was prepared.
  • Candida colonies were picked from the streak plate and a suspension was prepared in RPMI medium equal to a 0.5 McFarland standard, then diluted 1 :100 in RPMI and transferred to compartments of sterile reservoirs divided by length (Beckman Coulter).
  • Aspergillus isolates previously prepared and quantitated suspensions were used to make dilutions in RPMI to reach 20X the final concentration. These dilutions were also transferred to compartments of sterile reservoirs divided by length (Beckman Coulter). The final concentration of the Aspergillus isolates was approximately 0.2-2.5 x 10 4 CFU/mL.
  • the Biomek 2000 was used to inoculate the plates. Daughter plates were placed on the Biomek 2000 work surface reversed so that inoculation took place from low to high drug
  • the Biomek 2000 delivered 10 ⁇ of standardized inoculum into each well.
  • the wells of the daughter plates ultimately contained 1 85 ⁇ of RPMI, 5 ⁇ of drug solution, and 10 ⁇ of inoculum.
  • the final concentration of DMSO in the test well was 2.5% for the evaluated comparators and 1 .25% for the investigational agents. Plates were stacked 3 high, covered with a lid on the top plate, placed into plastic bags, and incubated at 35 S C for approximately 24-48 hr prior to reading. Plates were read when inoculum was confluent in growth wells. Plates were viewed from the bottom using a plate viewer. An un-inoculated solubility control plate was observed for evidence of drug precipitation.
  • MICs were read where visible growth of the organism was inhibited. MECs were read where the growth shifted to a small, rounded, compact hyphal form as compared to the hyphal growth seen in the growth control well. MIC and MEC values are shown in Table 4 below.
  • Example 21 Compound 1 mediates binding of rabbit anti-Rha antibody to Aspergillus fumigatus
  • FIGS. 1 A and 1 B show binding of the secondary anti-rabbit lgG1 (red fluorescence) to rabbit anti-Rha antibodies which in turn are bound to A. fumigatus hyphae.
  • CD101 acetate which lacks the rhamnose of Compound 1 ; the structure of CD101 acetate is shown in Example 10.
  • CD101 acetate which lacks the rhamnose of Compound 1 ; the structure of CD101 acetate is shown in Example 10
  • Compound 1 is capable of coordinating the binding of anti-Rha antibodies to A. fumigatus hyphae. This is considered the first step in an immune response against the fungal pathogen.
  • Example 22 Inoculation of rabbits with OVA-Rha-linked vaccine, isolation of serum and purification of anti-Rha antibodies
  • Step a Synthesis of N-(2- ⁇ 2-[(6-deoxy-alpha-L-mannopyranosyl)oxy]ethoxy ⁇ ethyl)-4- [(2,5-dioxopyrrolidin-1-yl)oxy]-4-oxobutanamide
  • CFA Complete Freund's Adjuvant
  • IFA Sigma F5506 Incomplete Freund's Adjuvant
  • 6-Aminohexyl-Agarose (5 mL, 4% crosslinked beaded agarose, -5 ⁇ per mL) suspended in saline was centrifuged (3500 rpm for 5 min), then decanted to remove water. The resulting solid was suspended in DMF (4 x 15 mL), centrifuged (3500 rpm for 5 min) and decanted. The agarose was resuspended in DMF (1 mL), and treated with INT-2 (0.140 g, 0.40 mmol), followed by DIEA (0.21 mL, 1 .20 mmol), and HATU (0.152 g, 0.40 mmol).
  • Serum from immunized rabbits was diluted 2-fold in 2X PBS pH 7.4.
  • the solution was passaged over the solid supported a-L-rhamnose column (from Step a) by gravity flow followed by a wash step using 10 CV of 1 X PBS pH 7.4.
  • Protein was eluted using 20 mM Glycine Buffer pH 2.0 and immediately adjusted to a neutral pH by the addition of 1 M Tris pH 9.0.
  • the eluate was buffer exchanged with 1 X PBS pH 7.4 and concentrated in Amicon centrifugal concentrators (10K MWCO).
  • the presence of IgG was determined by reducing and non-reducing SDS-PAGE and quantitated using a NanoDrop 2000 Spectrophotometer.
  • the resultant purified antibodies can be used in place of serum adjusting for relative antibody titers.
  • Example 23 Efficacy of Compound 1 in a Mouse Candidiasis Model
  • Test articles Compound 1 , caspofungin acetate and purified rabbit anti-rhamnose antibodies (rAbs) were stored at 4 °C. Compound 1 was dissolved in 10% DMSO/1 % Tween 20 in water for injection (WFI) to generate five doses of 0.03, 0.1 , 0.3, 1 and 3 mg/kg and caspofungin at 0.1 mg/kg was dissolved in WFI before using. A pre-formulated solution of purified rabbit anti-Rha antibodies was injected 0.1 mL/mouse by intravenous (IV) injection. The dosing volume was 10 mL/kg by intraperitoneal (IP) administration for Compound 1 and caspofungin acetate in the study.
  • IV intravenous
  • IP intraperitoneal
  • Candida albicans (ATCC R303) was cryopreserved as single-use working stock cultures which stored at -80 S C. A 0.1 mL aliquot stock was transferred to a sabouraud agar (SA) plate and incubated at 35-37 S C overnight. The culture was re-suspended with 1 mL cold PBS (>3.0 x 10 9 CFU/mL, OD 6 2o 3.0-3.2) and diluted with PBS to 1 x 10 4 CFU/mL. The actual colony counts were determined by plating dilutions to sabouraud agar plates followed by 20 - 24 hr incubation. The actual inoculum count was 2.93 x 10 4 CFU/mL.
  • mice Male ICR mice weighing 22 ⁇ 2 g were acclimated for 3 days prior to use. All animals were maintained in a hygienic environment with controlled temperature (20 - 24 S C), humidity (30% - 70%) and 12 hours light/dark cycles. Free access to sterilized standard lab diet [MFG (Oriental Yeast Co., Ltd., Japan)] and autoclaved tap water were granted.
  • MFG Oriental Yeast Co., Ltd., Japan
  • Immune suppression was induced by two intraperitoneal injections of cyclophosphamide at 150 mg/kg 4 days (Day -4) and at 100 mg/kg 1 day before inoculation (Day -1 ). On Day 0, animals were inoculated intravenously (0.1 mL/mouse) with C. albicans (R303), 2.93 x 10 3 CFU per mouse.
  • Purified rabbit anti-Rha antibodies in PBS (pH 7.4) were injected once at 100 ⁇ / ⁇ by intravenous administration 1 day prior to C. albicans challenge. On day 0, Compound 1 was intraperitoneally administered at 0.03, 0.1 , 0.3, 1 and 3 mg/kg 2 hours post-inoculation to the rAbs untreated/treated animals. Caspogungin acetate at 0.1 mg/kg was administered IP 2 hours after inoculation. The dosing volume was 10 mL/kg for all groups, (see figure above)
  • the animals were euthanized by CO2 asphyxiation 2 or 72 hr post-inoculation. Paired kidneys were harvested and weighed. The harvested kidneys were homogenized in 1 mL of PBS, pH 7.4, with a Polytron homogenizer. A 0.1 mL aliquot of each homogenate was used for serial 10-fold dilutions and plated onto SA plates for fungal enumeration. The fungal counts (CFU/g) in kidneys were calculated and the percentage decrease in counts compared to the corresponding vehicle control was calculated with the following formula:
  • amphotericin B was dissolved in 0.9% saline and Compound 1 in 1 0% DMSO/1 % Tween 20/0.9% NaCI.
  • mice Female ICR mice weighing 22 ⁇ 2 g were maintained in a well-controlled temperature (20 - 24 °C) and humidity (30% - 70%) environment with 12 hours light/dark cycles. Free access to standard lab diet [MFG (Oriental Yeast Co., Ltd., Japan)] and autoclaved tap water were granted. Animals were immunosuppressed by three intraperitoneal injections of cyclophosphamide (the first injection was at 6 mg/mouse 3 days before inoculation, the second and third injections were at 2 mg/mouse 1 and 4 days after inoculation. On Day 0, animals were inoculated (0.1 mL/mouse IV) with A. fumigatus (ATCC 13073), 3.65 x 10 4 CFU per mouse.
  • MFG Oriental Yeast Co., Ltd., Japan
  • Example 25 Efficacy of Compound 1 in a Murine Model of Invasive Candidiasis
  • the objective of this study was to evaluate the in vivo efficacy of Compound 1 as therapy against invasive pulmonary candidiasis in a murine model.
  • mice were inoculated intravenously (IV) through the lateral tail vein with a susceptible Candida albicans isolate.
  • IV intravenously
  • AB polyclonal antibody
  • Treatment with each antifungal began one day post-challenge and continued through Day 7. Survival and fungal burden arms were included.
  • a placebo (vehicle) control was included in each arm.
  • Isolate A Candida albicans isolate, ATCC 90028, was utilized that is susceptible to antifungal agents. Isolates were sub-cultured at 37°C for 48 hours on Sabouraud dextrose agar twice. Prior to inoculation, isolates taken from the second subculture were placed into brain heart infusion broth and grown overnight at 37°C with shaking at 200 rpm. Cells were then collected by centrifugation and washed three times in sterile saline. Animal Model. Outbred ICR mice (Envigo) were housed 5 per cage and had access to food and water ad libitum. On Day 0, mice were infected intravenously with 0.2 ml_ of C.
  • the starting inoculum was determined by counting Candida cells using a hemocytometer and adjusting to the target number of cells for each isolate.
  • serial dilutions were prepared in saline and plated onto Sabouraud dextrose agar plates and incubated at 37°C in order to verify the number of viable Candida cells.
  • Antifungal Treatment experiments were used to evaluate the in vivo efficacy of Compound 1 against invasive candidiasis. Mice were administered the polyclonal antibody on Day -1 relative to inoculation. Treatment with antifungals began 24 hours following inoculation and were continued through Day 7 post-inoculation. Compound 1 was administered by intraperitoneal (IP) injection at doses of 3 mg/kg, 10 mg/kg, and 30 mg/kg once daily (QD). Survival and fungal burden arms were included in the study. Treatment groups and the number of animals in each group and each arm are shown in the Table 8.
  • IP intraperitoneal
  • mice were humanely euthanized on Day 8 post-inoculation.
  • Kidneys were harvested, weighed, and homogenized in sterile saline supplemented with antibiotics. Serial dilutions of the tissue homogenates were prepared and plated in duplicate onto Sabouraud dextrose agar. After 24 hours of incubation at 37°C, the colonies were counted and the numbers of colony forming units (CFU) per gram of tissue calculated. Fungal burden was also measured in mice as they succumb to infection in the survival arm and in those that survive to the study endpoint (Day 21 ). Blood was also collected by cardiac puncture on Day 8 in the fungal burden arm of mice administered Compound 1 . Plasma was separated and immediately frozen. Compound 1 concentrations were measured in plasma and kidney tissue samples.
  • Kidney fungal burden in the fungal arm is shown in Table 10.
  • Kidney fungal burden in the survival arm is shown in Table 1 1 .
  • Example 26 Efficacy of Compound 1 in a Murine Model of Invasive Pulmonary Aspergillosis
  • the objective of this study was to evaluate the in vivo efficacy of Compound 1 as therapy against invasive pulmonary aspergillosis in a murine model of invasive pulmonary aspergillosis.
  • mice immunosuppressed mice for seven days at two different doses (beginning two days after the administration of the polyclonal antibody).
  • Plasma and lung samples were collected at various time points after the last dose and concentrations of Compound 1 were measured. The tolerability of Compound 1 was also evaluated.
  • Compound 1 was administered as treatment against established pulmonary infection.
  • a single dose of the polyclonal antibody (AB) that is absent in mice was administered on Day -1 relative to infection.
  • Compound 1 was administered at different doses beginning one day after pulmonary inoculation with A. fumigatus.
  • a placebo (vehicle) control group was also included. Endpoints included survival and changes in pulmonary fungal burden.
  • Preliminary Pharmacokinetic / Dose Tolerability Study A preliminary pharmacokinetic / dose tolerability study was conducted with Compound 1 . Uninfected male ICR mice were immunosuppressed, as described below for the infection model. Mice were administered a single dose of the polyclonal antibody by intravenous injection.
  • mice were administered Compound 1 at the highest and lowest anticipated doses IV and IP doses for seven days. After the morning dose on Day 7, blood was collected by cardiac puncture from three mice per time point in each group, and the plasma was separated and frozen. Lung samples were also collected from the mice at these time points and stored frozen. Compound 1 concentrations were measured in the frozen plasma and lung samples. Mice were also monitored multiple times per day, including close observation following IV and IP administration. These observations, along with daily weights, were used to evaluate the tolerability of Compound 1 in immunosuppressed mice. The number of mice per time point for each dose of Compound 1 is shown in Table 12.
  • Compound 1 concentrations were measured in the frozen plasma and lung samples.
  • Compound 1 concentrations as measured in frozen plasma are shown in FIGs. 2A and 4A.
  • FIGs. 3A and 4A Compound 1 IV
  • FIGs.3B and 4B Compound 1 IP
  • the mean ratio of Compound 1 concentration in lung/plasma are shown in FIGs. 4A and 4B.
  • Compound 1 showed a sustained lung tissue/plasma ratio of 1 .

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Abstract

Des compositions et des procédés pour le traitement d'infections fongiques comprennent des composés contenant un inhibiteur de β-1,3-glucane synthase conjugué de manière covalente à une ou plusieurs fractions de monosaccharide ou d'oligosaccharide. En particulier, des composés peuvent être utilisés dans le traitement d'infections fongiques provoquées par un champignon du genre Candida ou Aspergillus.
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US10369188B2 (en) 2016-01-08 2019-08-06 Cidara Therapeutics, Inc. Methods for preventing and treating pneumocystis infections
US10702573B2 (en) 2012-03-19 2020-07-07 Cidara Therapeutics, Inc. Dosing regimens for echinocandin class compounds
CN113214094A (zh) * 2021-04-26 2021-08-06 潍坊天福化学科技有限公司 一种伏格列波糖的合成方法
US11197909B2 (en) 2017-07-12 2021-12-14 Cidara Therapeutics, Inc. Compositions and methods for the treatment of fungal infections
US11524980B2 (en) 2018-06-15 2022-12-13 Cidara Therapeutics, Inc. Synthesis of echinocandin antifungal agent
US11712459B2 (en) 2016-03-16 2023-08-01 Cidara Therapeutics, Inc. Dosing regimens for treatment of fungal infections
US12060439B2 (en) 2018-10-25 2024-08-13 Napp Pharmaceutical Group Limited Polymorph of echinocandin antifungal agent
US12344680B2 (en) 2011-03-03 2025-07-01 Napp Pharmaceutical Group Limited Antifungal agents and uses thereof

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US20160213742A1 (en) * 2013-09-04 2016-07-28 Cidara Therapeutics, Inc. Compositions and methods for the treatment of fungal infections

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US20160045611A1 (en) * 2013-03-15 2016-02-18 Arizona Board Of Regents, For And On Behalf Of, Arizona State University Sugar-linker-drug conjugates
US20160213742A1 (en) * 2013-09-04 2016-07-28 Cidara Therapeutics, Inc. Compositions and methods for the treatment of fungal infections

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12344680B2 (en) 2011-03-03 2025-07-01 Napp Pharmaceutical Group Limited Antifungal agents and uses thereof
US10702573B2 (en) 2012-03-19 2020-07-07 Cidara Therapeutics, Inc. Dosing regimens for echinocandin class compounds
US11654196B2 (en) 2012-03-19 2023-05-23 Cidara Therapeutics, Inc. Dosing regimens for echinocandin class compounds
US10369188B2 (en) 2016-01-08 2019-08-06 Cidara Therapeutics, Inc. Methods for preventing and treating pneumocystis infections
US10780144B2 (en) 2016-01-08 2020-09-22 Cidara Therapeutics, Inc. Methods for preventing and treating pneumocystis infections
US11712459B2 (en) 2016-03-16 2023-08-01 Cidara Therapeutics, Inc. Dosing regimens for treatment of fungal infections
US11197909B2 (en) 2017-07-12 2021-12-14 Cidara Therapeutics, Inc. Compositions and methods for the treatment of fungal infections
US11819533B2 (en) 2017-07-12 2023-11-21 Cidara Therapeutics, Inc. Compositions and methods for the treatment of fungal infections
US11524980B2 (en) 2018-06-15 2022-12-13 Cidara Therapeutics, Inc. Synthesis of echinocandin antifungal agent
US12146006B2 (en) 2018-06-15 2024-11-19 Napp Pharmaceutical Group Limited Synthesis of echinocandin antifungal agent
US12060439B2 (en) 2018-10-25 2024-08-13 Napp Pharmaceutical Group Limited Polymorph of echinocandin antifungal agent
CN113214094A (zh) * 2021-04-26 2021-08-06 潍坊天福化学科技有限公司 一种伏格列波糖的合成方法

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