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EP0455719A1 - COMPOSITION SYNERGIQUE COMPRENANT UN PEPTIDE MAGAININE ET UN PEPTIDE PGLa - Google Patents

COMPOSITION SYNERGIQUE COMPRENANT UN PEPTIDE MAGAININE ET UN PEPTIDE PGLa

Info

Publication number
EP0455719A1
EP0455719A1 EP90902924A EP90902924A EP0455719A1 EP 0455719 A1 EP0455719 A1 EP 0455719A1 EP 90902924 A EP90902924 A EP 90902924A EP 90902924 A EP90902924 A EP 90902924A EP 0455719 A1 EP0455719 A1 EP 0455719A1
Authority
EP
European Patent Office
Prior art keywords
peptide
derivative
analogue
pgla
magainin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP90902924A
Other languages
German (de)
English (en)
Other versions
EP0455719A4 (en
Inventor
Michael Zasloff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Childrens Hospital of Philadelphia CHOP
Original Assignee
Magainin Sciences Inc
Childrens Hospital of Philadelphia CHOP
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Magainin Sciences Inc, Childrens Hospital of Philadelphia CHOP filed Critical Magainin Sciences Inc
Publication of EP0455719A1 publication Critical patent/EP0455719A1/fr
Publication of EP0455719A4 publication Critical patent/EP0455719A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • This invention relates to biologically active peptides, and more particularly to compositions and uses involving combinations of biologically active peptides.
  • a composition which includes (a) a magainin peptide or analogue or derivative thereof; and (b) at least one member selected from the group consisting of (i) a PGLa peptide or analogue or derivative thereof and (ii) an XPF peptide or analogue or derivative thereof.
  • the magainin peptide or analogue or derivative thereof, as well as the PGLa peptide or analogue or derivative thereof and the XPF peptide or analogue or derivative thereof may be amide terminated or
  • a host comprises administering to a host both (a) a magainin peptide or analogue or derivative thereof and (b) at least one member selected from the group consisting of (i) an XPF peptide or analogue or derivative thereof and (ii) a PGLa peptide or analogue or derivative thereof.
  • components (a) and (b) may be administered in separate
  • components (a) and (b) may be administered in a single composition.
  • components (a) and (b) may be administered in a single composition.
  • components (a) and (b) may be administered in a single composition.
  • the target for example, may be bacteria, fungi,
  • the synergism may be due to association of the peptides to a novel multimeric complex, such as a dimer, which possesses markedly increased membrane affinity for the target cells.
  • the complex formed between the two peptides is believed to possess potent membrane disruptive properties. It is believed that the peptides have the capacity to organize within target cell membranes and to disturb cellular functions.
  • the magainin peptide or analogue or derivative thereof is employed in a dosage of from about lmg to about 100mg per kilogram of host weight, when administered systemically.
  • the magainin peptide is used in a dosage of from about lmg to about 100mg per kilogram of host weight, when administered systemically.
  • the magainin peptide is used in a dosage of from about lmg to about 100mg per kilogram of host weight, when administered systemically.
  • the magainin peptide is used in a dosage of from about lmg to about 100mg per kilogram of host weight, when administered systemically.
  • the PGLa peptide or analogue or derivative thereof, when administered systemically, is
  • the PGLa peptide is administered in a dosage of from about lmg to about 100mg per kilogram of host weight.
  • the PGLa peptide is administered in a concentration of from about 0.5% to about .50%.
  • the XPF peptide or analogue or derivative thereof, when administered systemically, is
  • the XPF peptide or analogue or derivative thereof is administered in a concentration of from about .05% to about .50%.
  • this combination of peptides in accordance with the present invention is effective as an antibiotic, and may be employed to inhibit, prevent or destroy the growth or proliferation of microbes, such as bacteria, fungi, viruses or the like. Similarly, such compositions may be employed as an anti-viral composition to inhibit, prevent or destroy the growth or proliferation of viruses.
  • compositions may also be employed as a spermicide to inhibit, prevent or destroy the
  • compositions may also be employed as anti-tumor agents to inhibit the growth of or destroy tumors.
  • compositions have a broad range of potent antibiotic activity against a plurality of
  • microorganisms including gram-positive and
  • compositions may be employed for treating or controlling microbial infection caused by organisms which are sensitive to such composition.
  • treatment may comprise administering to a host organism or tissues acceptable to or affiliated with a microbial infection an anti-microbial amount of magainin peptide or analog or derivative thereof and of PGLa peptide or XPF peptide.
  • compositions may also be used as
  • preservatives or sterilants for materials susceptible to microbial contamination.
  • the magainin peptide may be, for example, a magainin such as magainin I, II or III or an analogue or derivative thereof.
  • the magainin peptides may be, for example, a magainin such as magainin I, II or III or an analogue or derivative thereof.
  • R 11 is a hydrophobic amino acid
  • R 12 is a basic hydrophilic amino acid
  • R 13 is a hydrophobic, neutral hydrophilic or basic hydrophilic amino acid
  • R 14 and R 14a are hydrophobic or basic hydrophilic amino acids
  • R 15 is glutamic or aspartic acid, or a hydrophobic or basic hydrophilic amino acid
  • n is
  • R 13 is a
  • R 14a is a hydrophobic amino acid
  • R 15 is glutamic acid or aspartic acid.
  • the hydrophobic amino acids may be selected from the class consisting of Ala, Cys, Phe, Gly, Ile, Leu, Met, Val, Trp, and Tyr.
  • the neutral hydrophilic amino acids may be selected from the class consisting of Asn, Gln, Ser, and Thr.
  • the basic hydrophilic amino acids may be selected from the class consisting of Lys, Arg, and His, and ornithine (0).
  • the magainin peptides generally include at least seventeen amino acids and may also include up to forty amino acids. Accordingly, the hereinabove described basic peptide structure of a magainin peptide may include additional amino acids at the amino end or at the carboxyl end, or at both ends.
  • a magainin peptide may include the following structure: -Y 12 -X 12 - where X 12 is the hereinabove described basic
  • R 11 , R 12 , R 14 and R 14a are as previously defined.
  • a magainin peptide may also have the following structure
  • R 16 where R 16 is a basic hydrophilic amino acid or asparagine or glutamine.
  • hydrophilic amino acid a hydrophobic amino acid, or a basic hydrophilic amino acid.
  • R 17 is a neutral hydrophilic amino acid.
  • a magainin peptide may also have the following structure:
  • the magainin peptides may also include the
  • the magainin peptide may also include the
  • R 11 , R 14 , R 14a , R 15 , R 16 , and R 17 are as hereinabove described, and n is 0 or 1, and each n may be the same or different.
  • the magainin peptides generally include at least fourteen amino acids and may include up to forty amino acids.
  • a magainin peptide preferably has 22 or 23 amino acids. Accordingly, the hereinabove
  • described basic peptide structures of a magainin peptide may include additional amino acids at the amino end or at the carboxyl end, or at both ends.
  • magainin peptides having the following primary sequence (expressed as a single letter code) as well as appropriate analogues and deriatives thereof:
  • the peptide employed in conjunction with the magainin peptide is a PGLa peptide or an XPF peptide.
  • a PGLa peptide is either PGLa or an analogue or derivative thereof.
  • the PGLa peptides preferably include the following basic structure X 14 :
  • the PGLa peptides generally include at least seventeen amino acids and may include as many as forty amino acids. Accordingly, the hereinabove described basic peptide sturcture for a PGLa peptide may include additional amino acids at the amino end or at the carboxyl end or at both the amino and carboxyl end.
  • a PGLa peptide may have the following sturcture:
  • PGLa peptide may also have the following structure:
  • a PGLa peptide may also have the following structure: (Y 14 ) a -X 14 -(Z 14 ) b
  • X 14 ; Y 14 and Z 14 are as previously defined, a is 0 or 1 and b is 0 or 1.
  • An XPF peptide is either XPF or an analogue or derivative thereof.
  • the XPF like peptides preferably include the following basis peptide structure X, 16 :
  • R 11 , R 12 , R 14 , R 15 and R 17 are as previously defined and R 18 is glutamine or
  • n 0 or 1.
  • the XPF peptides generally include at least nineteen amino acids and may include up to forty amino acids. Accordingly, the hereinabove described basic peptide structure of XPF may include additional amino acids at the amino end, or at the carboxyl end or at both the amino and carboxyl ends.
  • an XPF peptide may include the following structure:
  • R 11 and R 14 are as previously defined.
  • An XPF peptide may include the follwing
  • An XPF peptide may also have the followingstructure:
  • XPF or PGLa peptides which are characterized by the following primary amino acid sequence (single letter amino acid code);
  • PGLa GMASKAGAIAGKIAKVALKAL (NH 2 )
  • MGN2 Magainin 2
  • PGLa peptide a mixture of MGN2 and PGLa in a 1:1 molar ratio was added to the broth in increasing
  • MIC minimal inhibitory concentration
  • the concentration of S. aureus killed by 100 ⁇ g/ml of preparations of Magainin 2, PGLa, and a preparation of Magainin 2 and PGLa in a 1:1 molar ratio is noted. It was found that a 100 ⁇ g/ml preparation of Magainin 2 does not completely kill S. aureus at concentrations of bacteria at less than 10 bacterial/ml. Similar results were also obtained for PGLa.
  • the 100 ⁇ g/ml preparation of the equimolar miture of Magainin 2 and PGLa achieved complete killing of a concentration of 10 5 bacteria/ml.
  • the equimolar mixture of Magainin 2 and PGLa achieved an increase in bactericidal potency over either peptide by greater than 10 5 .
  • Magainin 2 (mole PGLa/mole MGN2) were added to the broths to increasing concentration of peptide
  • bactericidal activity is achieved when an equimolar mixture of PGLa and Magainin 2 is added to the S.
  • peptide combinations in accordance with the present invention, may be employed for treating a wide variety of hosts.
  • peptide combinations in accordance with the present invention, may be employed for treating a wide variety of hosts.
  • a host may be an animal, and such animal may be a human or non-human animal.
  • the magainin peptide and the PGLa and/or XPF peptide may be employed together in a single composition, or in separate compositions.
  • the magainin peptide and PGLa and/or XPF peptide may be employed in a wide variety of pharmaceutical compositions in combination with a non-toxic
  • compositions may be used.
  • a pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or physiological saline solution.
  • Such pharmaceutical compositions may be used
  • topically or systemically may be in any suitable form such as a liquid, solid, semi-solid, injectable solution, tablet, ointment, lotion, paste, capsule, or the like. It is also contemplated that the magainin peptide and the PGLa and/or XPF peptide may be delivered or administered in different forms. The magainin peptide and PGLa and/or XPF peptide may also be used in combination with adjuvants, protease inhibitors, or compatible drugs where such a
  • microorganisms including protozoa viruses, and the like.
  • the peptide(s) of the present invention may be administered to a host; in particular an animal, in an effective antibiotic and/or anti-tumor and/or anti-viral and/or anti-microbial and/or a spermicidal amount.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne une composition comprenant un peptide de magainine ou un analogue ou un dérivé de celui-ci, ainsi qu'au moins un élément sélectionné dans le groupe composé d'un peptide de PGLa ou d'un analogue ou d'un dérivé de celui-ci, et un peptide de XPF ou un analogue ou un dérivé de celui-ci. On emploie la composition en tant que produit pharmaceutique.
EP19900902924 1989-01-30 1990-01-25 Composition and treatment with peptide combinations Withdrawn EP0455719A4 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US30298589A 1989-01-30 1989-01-30
US302985 1989-01-30
US34689489A 1989-05-03 1989-05-03
US346894 1989-05-03

Publications (2)

Publication Number Publication Date
EP0455719A1 true EP0455719A1 (fr) 1991-11-13
EP0455719A4 EP0455719A4 (en) 1992-07-08

Family

ID=26973198

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19900902924 Withdrawn EP0455719A4 (en) 1989-01-30 1990-01-25 Composition and treatment with peptide combinations

Country Status (5)

Country Link
EP (1) EP0455719A4 (fr)
JP (1) JPH04506056A (fr)
AU (1) AU5042890A (fr)
CA (1) CA2007913A1 (fr)
WO (1) WO1990008552A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU648140B2 (en) * 1991-02-01 1994-04-14 Virtual Drug Development, Inc. Reverse antimicrobial peptides and antimicrobial compositions
WO1992022317A1 (fr) * 1991-06-12 1992-12-23 Magainin Pharmaceuticals, Inc. Composition de peptides biologiquement actifs presentant des substitutions au niveau de leur terminaison c et traitement a l'aide de ces peptides
US5593866A (en) * 1992-08-21 1997-01-14 The University Of British Columbia Cationic peptides and method for production
US6057291A (en) 1995-06-02 2000-05-02 University Of British Columbia Antimicrobial cationic peptides
JP3860838B2 (ja) 1995-08-23 2006-12-20 ユニバーシティー オブ ブリティッシュ コロンビア 抗微生物性陽イオン性ペプチドおよびそのスクリーニング方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988006597A1 (fr) * 1987-03-04 1988-09-07 The United States Of America, As Represented By Th Composes bioactifs synthetiques nouveaux et procede d'obtention d'effets bioactifs

Also Published As

Publication number Publication date
WO1990008552A1 (fr) 1990-08-09
AU5042890A (en) 1990-08-24
EP0455719A4 (en) 1992-07-08
CA2007913A1 (fr) 1990-07-30
JPH04506056A (ja) 1992-10-22

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