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WO2018038168A1 - Peptide de liaison à l'hémagglutinine et agent prophylactique/thérapeutique pour une infection par le virus de la grippe qui contient celui-ci - Google Patents

Peptide de liaison à l'hémagglutinine et agent prophylactique/thérapeutique pour une infection par le virus de la grippe qui contient celui-ci Download PDF

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Publication number
WO2018038168A1
WO2018038168A1 PCT/JP2017/030158 JP2017030158W WO2018038168A1 WO 2018038168 A1 WO2018038168 A1 WO 2018038168A1 JP 2017030158 W JP2017030158 W JP 2017030158W WO 2018038168 A1 WO2018038168 A1 WO 2018038168A1
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Prior art keywords
tet
peptide
binding
hemagglutinin
pvf
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Japanese (ja)
Inventor
西川　喜代孝
美帆 高橋
純平 近江
山下　誠
桂 本郷
名取　泰博
ツェン チンイ
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Doshisha Co Ltd
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Doshisha Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof

Definitions

  • the present invention relates to a hemagglutinin-binding peptide and a preventive / therapeutic agent for an influenza virus infection containing the same.
  • Influenza A virus has a strong infectivity and causes a seasonal epidemic every year in Japan and around the world.
  • the emergence of a new influenza virus as seen in 2009 and the acquisition of the ability to infect humans with highly pathogenic avian influenza viruses such as H5N1 and H7N7 are feared, and a deadly pandemic is the world It is in a situation that is not strange anytime.
  • NA neuraminidase
  • HA hemagglutinin
  • NA hemagglutinin
  • HA plays an essential role in the virus growth cycle because it causes the target cell membrane to fuse with the virus membrane after the virus binds to the target cell and releases the viral gene into the cytoplasm. It has been known. HA is also the antigen of many influenza vaccines.
  • HA has a trimeric structure on the viral membrane, and one HA molecule recognizes and binds to one sialic acid molecule of glycoprotein or glycolipid present on the host cell membrane. Therefore, a total of 3 molecules of sialic acid can bind in the HA trimer.
  • the binding affinity increases several thousand times in the case of 3: 3 binding compared to 1: 1 binding, and this phenomenon is called “cluster effect”.
  • conventional techniques such as screening of low-molecular compound libraries and phage display screening are basically applicable only to 1: 1 interactions, and therefore accept HA that functions by exerting a cluster effect. In principle, it is extremely difficult to identify an inhibitor targeting a body binding site.
  • Patent Document 1 examples of obtaining low molecular weight compounds, and examples of obtaining HA-binding peptides by cyclic peptide library (Patent Document 1) and phage display screening (Patent Document 2) have been reported. Based on the above, no example has been reported in which an inhibitory peptide was isolated directly targeting the receptor binding site of HA.
  • the present inventors have so far developed a multivalent peptide library method as a technique for screening a molecule that inhibits a strong interaction based on the cluster effect (Patent Document 3). Since the multivalent peptide library has a structure in which four random peptide libraries are bonded to a tetravalent nuclear structure, the multivalent peptide library itself exhibits a cluster effect. In addition, the inventors have succeeded in developing inhibitory molecules for various molecules that function by exerting this cluster effect (for example, Patent Documents 4 to 6).
  • Patent Document 7 a technique for synthesizing multivalent peptides at a level of several hundreds on a sheet by applying the multivalent peptide library method.
  • JP 2013-71904 A Japanese Patent No. 5396111 Japanese Patent No.4744443 Japanese Patent No. 5635779 Japanese Patent No. 5718574 Japanese Patent No. 5754008 Japanese Patent No. 5718574
  • the present inventors can obtain a novel multivalent peptide that binds to HA by the cluster effect by using the multivalent peptide library method that has been established so far, targeting the receptor binding site of HA.
  • the inventors have conceived that a prophylactic / therapeutic agent for influenza virus infection can be established by using this multivalent peptide as an active ingredient, and the present invention has been completed.
  • the present invention has been made in view of the circumstances as described above, and an object of the present invention is to provide a novel hemagglutinin-binding peptide and a preventive / therapeutic agent for influenza virus infection containing the same.
  • the hemagglutinin-binding peptide of the present invention has a peptide motif of SEQ ID NO: 1 directly or with a spacer on each of four amino groups located at the end of a molecular nucleus structure formed by binding three lysines (Lys). It is characterized by being a tetravalent peptide couple
  • arginine (Arg) located on the N-terminal side of the peptide motif of SEQ ID NO: 1 is preferably substituted with a non-natural isomer (D-Arg).
  • the preventive / therapeutic agent for influenza virus infection according to the present invention is characterized by containing the hemagglutinin-binding peptide.
  • the hemagglutinin-binding peptide of the present invention can bind to hemagglutinin of influenza virus and inhibit the cytotoxic activity due to infection with influenza virus. Moreover, according to the preventive / therapeutic agent for influenza virus infection of the present invention, an influenza infection can be effectively prevented / treated.
  • A is a graph showing the molecular weight and purity of wild-type HA (WT-HA) and mutant HA (L194A-HA) immobilized on Ni beads by electrophoresis.
  • B is a figure which shows the measurement result of the binding activity with the fetuin of WT-HA and L194A-HA by ELISA method.
  • FIG. 3 is a diagram showing the chemical structure of a multivalent peptide library used in the screening of Example 2.
  • (A) is a table (table) showing the primary library used in the primary screening in Example 2 and the amino acid selectivity at each position.
  • B) is a diagram (table) showing the secondary library used in the secondary screening in Example 2 and the selectivity of amino acids at each position.
  • TKR-tet, RVH-tet candidate substances of HA inhibitor
  • a / PR / 8/34 at high titer
  • MOI 10
  • PVF-tet shows the results (molecular weight) of treating PVF-tet with trypsin. It is a figure which shows the result of having measured the coupling
  • FIG. 4 is a graph showing the results of measuring the cell viability after culturing for 48 hours by the WST method.
  • the hemagglutinin-binding peptide of the present invention contains the following molecular nucleus structure formed by combining three lysines (Lys).
  • the hemagglutinin-binding peptide of the present invention has the following peptide motif on each of the four —NH groups located at the end of the above-mentioned molecular nucleus structure: Sequence number 1: Arg-Arg-Pro-Val-Asn-His-Phe (RRPVNHF) Is a tetravalent peptide linked directly or via a spacer.
  • an embodiment of the hemagglutinin-binding peptide of the present invention has, for example, a sequence in each of four XXXX portions located at the end of a molecular nucleus structure composed of three lysines (Lys) in the following chemical formula:
  • a tetravalent peptide in which the peptide motif of No. 1 is incorporated is exemplified.
  • a tetravalent peptide in which four peptide motifs of SEQ ID NO: 1 are incorporated in the XXXX portion located at the end of a molecular nucleus structure composed of three lysines (Lys) may be referred to as “PVF-tet”.
  • the spacer is bonded to each of the four amino groups located at the end of the molecular nucleus structure, but each of the four amino groups is not involved with the spacer.
  • the peptide motif of SEQ ID NO: 1 can also be directly bound.
  • any spacer may be used as long as it does not impair the binding property to hemagglutinin, and the specific molecule and length are not limited and can be appropriately designed.
  • the spacer for example, a chain having an amino acid at the terminal and having a chain length of about 4 to 10 carbon atoms is preferable.
  • aminohexanoic acid [NH 2- (CH 2 ) 5 represented by “U” in the chemical formula 2 above. -COOH] (aminocaproic acid) can be preferably exemplified.
  • an amino acid contained in a spacer an alanine (A) can be illustrated, for example.
  • the hemagglutinin-binding peptide of the present invention may have a modifying molecule at each end of the peptide motif of SEQ ID NO: 1 incorporated in the XXXX part of Chemical Formula 2.
  • the peptide exemplified in Chemical Formula 2 above has MA (Met-Ala) at the end, which is exemplified in the examples described later at the time of screening. Two MAs are not necessarily required in the hemagglutinin-binding peptides of the present invention.
  • NH 2 is exposed to a positive charge when the terminal of the peptide motif is exposed, from the viewpoint of charge control, a molecule having no charge as a modifying molecule at each terminal of the peptide motif of SEQ ID NO: 1, It is also contemplated to bind hydrophobic molecules.
  • the hemagglutinin-binding peptide of the present invention can also protect the terminal NH 2 with an acetyl group for the purpose of stabilization in order to suppress degradation by proteases in the digestive tract when orally administering a therapeutic drug for influenza infection .
  • the modified molecule at the end of the peptide motif can be appropriately selected.
  • the method for producing the hemagglutinin-binding peptide of the present invention is not particularly limited, and can be produced by a known method such as using a peptide synthesizer.
  • the peptide motif (peptide compound) of SEQ ID NO: 1 incorporated into the hemagglutinin-binding peptide of the present invention can be synthesized by sequentially adding amino acids to a tetravalent nuclear structure, and can be conveniently performed in the same manner as monovalent peptide synthesis. Can be bulk synthesized.
  • arginine (Arg) located on the N-terminal side of the peptide motif of SEQ ID NO: 1 is substituted with a non-natural isomer (D-Arg) (hereinafter referred to as “the hemagglutinin-binding peptide”). “ (D) PVF-tet” may be indicated).
  • the influenza virus infects the respiratory tract because of the localization of HA-activating proteases such as trypsin-like protease in the respiratory tract.
  • the hemagglutinin-binding peptide (PVF-tet) of the present invention has the sequence of RRPVNHF (SEQ ID NO: 1) as an HA-binding motif. There is concern that the gap will be cut and the inhibitory effect will be diminished.
  • (D) PVF-tet in which arginine (Arg) located on the N-terminal side of the peptide motif of SEQ ID NO: 1 is substituted with a non-natural isomer (D-Arg) is: It has trypsin resistance and excellent stability.
  • the hemagglutinin-binding peptide of the present invention is a tetravalent peptide in which four peptide motifs of SEQ ID NO: 1 are bound to the ends of the molecular core structure formed by binding three lysines (Lys). Yes, it exerts strong binding affinity for hemagglutinin due to the cluster effect.
  • the composition containing the hemagglutinin-binding peptide of the present invention is a preventive or therapeutic agent for influenza infection ( It is useful as a pharmaceutical composition).
  • the hemagglutinin-binding peptide of the present invention can be used in kits for detection of influenza virus and diagnosis of influenza, etc., and elucidation of influenza virus infection caused by hemagglutinin, and various cell functions and life phenomena associated therewith. It is also considered to be used as a tool for this purpose.
  • the preventive and / or therapeutic agent for influenza infection of the present invention contains the hemagglutinin-binding peptide of the present invention as described above.
  • the hemagglutinin-binding peptide of the present invention can inhibit the binding of influenza virus to the host cell receptor, and can inhibit the cytotoxic activity of influenza virus.
  • influenza virus targeted by the preventive or therapeutic agent for influenza infection of the present invention is not particularly limited in its type or origin, and other types such as A type, B type or C type or human isolated type, pigs and horses, etc. Either a mammal separation type or a bird separation type may be used.
  • infection means a process in which a virus enters a living body through skin or mucous membrane, or a process in which a virus enters a cell by membrane fusion.
  • virus infection refers to a state in which a virus has entered a living body regardless of the presence or absence of symptoms.
  • prevention or treatment of influenza infection is used in its broadest sense. For example, alleviation or prevention of one or more symptoms associated with influenza virus infection, infection Inhibits the occurrence of later symptoms, prevents infection (delay or stop) of viruses in the living body, inhibits virus growth in the living body (delays or stops), reduces the number of viruses in the living body, etc. That means.
  • the administration form of the preventive or therapeutic agent for influenza infection of the present invention is not particularly limited, and may be orally or parenterally administered.
  • Parenteral administration includes, for example, intramuscular injection, intravenous injection, subcutaneous injection, transdermal administration, transmucosal administration (nasal, oral cavity, ocular, pulmonary, vaginal, transrectal) administration. Etc. can be illustrated.
  • the prophylactic or therapeutic agent for influenza infection of the present invention may be prepared by using the hemagglutinin-binding peptide as an active ingredient as it is, or may be formulated by adding a pharmaceutically acceptable carrier, excipient, additive or the like.
  • a pharmaceutically acceptable carrier for example, injections
  • dispersions for example, injections
  • suspensions tablets, pills, powders, suppositories
  • powders fine granules, granules, capsules, syrups, lozenges
  • Examples include inhalants, ointments, eye drops, nasal drops, ear drops, and poultices.
  • Formulation includes, for example, excipients, binders, disintegrants, lubricants, solubilizers, solubilizers, colorants, flavoring agents, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjustments It can be carried out by a conventional method using an agent, preservative, antioxidant and the like as appropriate.
  • ingredients used for formulation include purified water, saline, phosphate buffer, dextrose, glycerol, ethanol and other pharmaceutically acceptable organic solvents, animal and vegetable oils, lactose, mannitol, glucose, sorbitol, crystalline cellulose , Hydroxypropyl cellulose, starch, corn starch, silicic anhydride, magnesium magnesium silicate, collagen, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, sodium carboxymethyl cellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch , Pectin, methylcellulose, ethylcellulose, xanthan gum, gum arabic, tragacanth, casein, agar, polyethylene glycol, diglyme Phosphorus, glycerol, propylene glycol, vaseline, paraffin, octyldodecyl myristate, isopropyl myristate
  • the preventive or therapeutic agent for influenza infection of the present invention is administered to mammals (eg, humans, mice, rats, guinea pigs, rabbits, dogs, horses, monkeys, pigs, etc.), particularly humans.
  • mammals eg, humans, mice, rats, guinea pigs, rabbits, dogs, horses, monkeys, pigs, etc.
  • the dose varies depending on the age, sex, body weight, sensitivity difference, administration method, administration interval, type of active ingredient, type of formulation, and is not particularly limited.
  • 10 mg to 200 mg, preferably 200 mg to 500 mg It can be given in several or several divided doses.
  • 50 mg to 200 mg may be administered once or divided into several times depending on the weight of the patient.
  • the hemagglutinin-binding peptide and the prophylactic / therapeutic agent for influenza infection of the present invention are not limited to the above-described embodiments, and are appropriately designed within a range that does not impair the hemagglutinin binding ability or the cytotoxic activity inhibitory effect due to influenza infection. can do.
  • the method for preventing / treating influenza infection of the present invention is directed to the above-mentioned preventive / therapeutic agent for influenza infection (for example, human, mouse, rat, guinea pig, rabbit, dog, horse, monkey, pig, etc.). It is characterized by administration.
  • the hemagglutinin-binding peptide and the preventive / therapeutic agent for influenza infection of the present invention will be described in detail together with examples.
  • the hemagglutinin-binding peptide and the preventive / therapeutic agent for influenza infection of the present invention are limited to the following examples. Is not to be done.
  • FIG. 2 shows the structure of a multivalent peptide library used for screening.
  • M represents Met, Ala, and aminocaproic acid, respectively.
  • XXXX indicates a library portion, and X (degenerate position) indicates that synthesis was performed using a mixture of 19 amino acids other than Cys.
  • each HA-immobilized bead (HA amount 250 ⁇ g) and a multivalent peptide library (300 ⁇ g) were incubated in 200 ⁇ l PBS at 4 ° C. for 18 hours. After washing the beads, peptides bound to each HA were eluted with 30% acetic acid, and after recovery, amino acid sequencing was performed sequentially from the N-terminal. For each degenerate position, the molar ratio of 19 detected amino acids was calculated and corrected so that the sum was 19.
  • TKR-tet a tetravalent peptide compound in which the peptide motif of SEQ ID NO: 2 is incorporated into the XXXX part of the multivalent peptide library shown in FIG. 2, and the peptide of SEQ ID NO: 3
  • RVH-tet a tetravalent peptide compound in which the motif was incorporated into the XXXX part of the multivalent peptide library shown in FIG. 2 was synthesized as a candidate for an HA inhibitor.
  • Example 3 Identification of High Affinity HA Binding Motif Using Multivalent Peptide Sheet Screening Technique
  • a spot peptide synthesizer from intavis AG was used for synthesis of a multivalent peptide on a cellulose sheet.
  • the spacer length was adjusted by changing the FMOC-aminohexanoic acid to be added to 1, 2, 3 pieces.
  • one FMOC-Lys (FMOC) -OH is added, and a divalent peptide is obtained by performing an extension reaction so as to give the subsequent sequence equally to the two amino groups formed.
  • Lys (FMOC) -OH was reacted twice in succession, and a tetravalent peptide was synthesized by performing an elongation reaction on the four amino groups formed.
  • the sequence used after the addition of FMOC-Lys (FMOC) -OH was MA-RRRVNHH-A- containing the HA-binding motif RRRVNHH of SEQ ID NO: 3 determined previously.
  • the obtained sheet was blotted with WT-HA radiolabeled with 125 I, and the bound radioactivity was measured with BAS 2500 (GE Healthcare).
  • BAS 2500 GE Healthcare
  • the peptide synthesized on the sheet had the strongest binding to HA under the conditions that the synthesis density of the peptide was 100%, the spacer length was 1 aminohexanoic acid, and the valence was 4 (FIG. 5). . Therefore, in subsequent experiments, it was decided to synthesize peptides on cellulose sheets under these conditions.
  • the sequence of the HA-binding motif synthesized on the sheet is RRRVNHH of SEQ ID NO: 3 as the original sequence.
  • the original amino acid and Cys are excluded in order.
  • the obtained sheet was blotted with WT-HA and L194A-HA radiolabeled with 125 I (FIG. 6), and the bound radioactivity was measured with BAS 2500.
  • top 15 motifs with WT * WT / L194A values of 1.63 or higher are all substitutions of positions 2, 3, 4 or 7 of the original sequence. It was shown to be an important position.
  • the obtained sheet was blotted with 125 I-WT-HA and 25 I-L194A-HA (FIG. 7), and the bound radioactivity was measured with BAS 2500.
  • the product of the binding ratio showing L194-specific binding and the binding force to WT-HA was used as an index.
  • motifs are incorporated into the XXXX part of the multivalent peptide library shown in FIG. 2, and each is a tetravalent peptide compound, RR PV NH D -tet (hereinafter referred to as “PVD-tet”), RR PM NH H -tet (hereinafter referred to as ⁇ PMH-tet ''), RR PV NH N -tet (hereinafter referred to as ⁇ PVN-tet ''), RR PV NH F -tet (hereinafter referred to as ⁇ PVF-tet ''), RR PV NH P -tet (hereinafter referred to as “PVP-tet”) was synthesized as an influenza virus inhibitor candidate.
  • PVD-tet tetravalent peptide compound
  • PVF-tet showed the strongest inhibitory activity, and then PMH-tet, “PVN-tet”, and “PVP-tet” showed equivalent inhibitory activity (FIG. 8).
  • PVD-tet showed only weak inhibitory activity (FIG. 8).
  • each inhibitor of 300 ⁇ g / ml (RVH-tet, TKR-tet, PVD-tet, PVP-tet, PVN-tet, PMH-tet, PVF-tet, (D) PVF-tet,) Fetuin was added and the viability of the cells after 48 hours of culture was measured by the WST method. These compounds alone were confirmed to show little cytotoxicity after 48 hours (FIG. 9).
  • PVF-tet was the most promising anti-influenza drug and used for the following studies.
  • Example 5 Improvement of biological stability of PVF-tet
  • the HA protein is cleaved by protease and cleaved into subunits HA1 and HA2, and the fusion domain is It is necessary to be exposed.
  • the influenza virus infects the respiratory tract because of the localization of HA-activating proteases such as trypsin-like protease in the respiratory tract.
  • PVF-tet has the sequence of RRPVNHF (SEQ ID NO: 1) as an HA binding motif, when used as a therapeutic agent, trypsin-like protease cleaves between Arg at position 1 and Arg at position 2 and has an inhibitory effect.
  • PVF-tet (molecular weight 5572) was treated in the presence of 1 ⁇ g / ml trypsin at 37 ° C for 24 hours, and mass measurement was performed using a mass spectrometer.
  • was cleaved (molecular weight 4138) (FIG. 10).
  • (D) PVF-tet was prepared by replacing Arg at position 1 with D-Arg, which is a non-natural isomer, and the effect of trypsin treatment was similarly examined. As a result, it was shown that (D) PVF-tet was stably present without being cleaved even after trypsin treatment at 37 ° C. for 24 hours (FIG. 10).
  • Example 6 Inhibitory effects of PVF-tet and (D) PVF-tet on cytotoxic activity caused by influenza virus infection Inhibitors at various concentrations in MDCK cells (PVF-tet, (D) PVF-tet, RVH-tet)
  • PVF-tet and RVH-tet showed only weak inhibitory activity against low titer infection, whereas (D) PVF-tet efficiently inhibited cytotoxic activity (Fig. 13A). Under conditions of low titer infection, trypsin is added to the culture medium to promote virus growth. Therefore, PVF-tet and RVH-tet are degraded by trypsin during culture, and the inhibitory action is attenuated. However, (D) PVF-tet is resistant to trypsin, so it is considered that sufficient inhibitory activity could be exhibited even under these conditions.
  • (D) PVF-tet was shown to have the ability to efficiently inhibit the cytotoxic activity of the virus under both high titer infection and low titer infection.
  • the monomer peptide has almost no inhibitory activity at any concentration. It was shown not to be seen (FIG. 14).
  • PVF-tet and (D) PVF-tet have a cluster effect to bind to HA with high affinity and exhibit antiviral activity. Such a motif has been established by the present inventors. It was confirmed that it could not be identified except by the multivalent peptide screening method.
  • Influenza viruses can be efficiently infected after trans-respiratory infection by HA being cleaved by trypsin-like proteases present in the respiratory tract. Therefore, here, (D) PVF-tet having trypsin resistance was used.

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Abstract

L'invention concerne un peptide de liaison à l'hémagglutinine qui est un peptide tétravalent, dans lequel un motif peptidique représenté par SEQ ID NO : 1 est lié, directement ou avec un espaceur interposé entre eux, à chacun de quatre groupes amino situés aux bornes d'une structure de cœur de molécule formée par liaison de trois résidus de lysine (Lys) les uns aux autres.
PCT/JP2017/030158 2016-08-25 2017-08-23 Peptide de liaison à l'hémagglutinine et agent prophylactique/thérapeutique pour une infection par le virus de la grippe qui contient celui-ci Ceased WO2018038168A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020033327A (ja) * 2018-08-31 2020-03-05 学校法人同志社 破骨細胞分化制御ペプチド、および、破骨細胞分化に関連する疾患の含有する治療薬

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TWI858016B (zh) * 2019-02-18 2024-10-11 日商肽夢想股份有限公司 血球凝集素結合肽

Citations (7)

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WO2000059932A1 (fr) * 1999-03-31 2000-10-12 Otsuka Pharmaceutical Co., Ltd. Peptides se liant a l'hemagglutinine du virus de la grippe
JP2002284798A (ja) * 2001-03-27 2002-10-03 Keio Gijuku インフルエンザウイルス・ヘマグルチニン結合性ペプチド
JP2006101709A (ja) * 2004-09-30 2006-04-20 Glycomedics Inc ヘマグルチニン結合ペプチド、インフルエンザウイルス感染阻害剤、リポソーム、インフルエンザ治療薬、インフルエンザ予防薬
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