WO2008050830A1 - Agent anti-vih - Google Patents

Agent anti-vih Download PDF

Info

Publication number
WO2008050830A1
WO2008050830A1 PCT/JP2007/070807 JP2007070807W WO2008050830A1 WO 2008050830 A1 WO2008050830 A1 WO 2008050830A1 JP 2007070807 W JP2007070807 W JP 2007070807W WO 2008050830 A1 WO2008050830 A1 WO 2008050830A1
Authority
WO
WIPO (PCT)
Prior art keywords
glu
lys
leu
gln
amino acids
Prior art date
Application number
PCT/JP2007/070807
Other languages
English (en)
Japanese (ja)
Inventor
Nobutaka Fujii
Shinya Oishi
Masao Matsuoka
Eiichi Kodama
Original Assignee
Kyoto University
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 Kyoto University filed Critical Kyoto University
Priority to JP2008541019A priority Critical patent/JPWO2008050830A1/ja
Publication of WO2008050830A1 publication Critical patent/WO2008050830A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/21—Retroviridae, e.g. equine infectious anemia virus
    • 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
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates to a peptide having an excellent membrane fusion inhibitory action against HIV, and use of the peptide for prevention or treatment of AIDS virus-related diseases.
  • AIDS Abbreviation for acquired immune deficiency syndrome, and normal immunity against pathogens is obtained by infection with retroviruses that cause immunodeficiency (eg, HIV, SIV). It is a collective term for various diseases that develop when people stop working.
  • the C34 trimer with ⁇ -helical structure in HIV gp41 protein has a single helix structure.
  • a mechanism is known in which a hexamer is formed so as to wrap around a trimer of HR1, and fusion between the cell membrane of HIV and the cell membrane of the host cell occurs (see, for example, Non-Patent Document 1).
  • Drugs that target HR1 and prevent the formation of the above hexamer, such as T20 (trade name Fuzeon: polypeptide shown in SEQ ID NO: 3), are approved by the US FDA.
  • T20 trade name Fuzeon: polypeptide shown in SEQ ID NO: 3
  • Non-patent literature l Reviw: D.M.Eckert, P.S.Kim, Annu. Rev. Biochem. 2001, 70, 777-81 0
  • Non-Patent Document 2 Xu, et. Al., ANTIMICROBIAL AGENT AND CHEMOTHERAPY, Mar, 2005, 49, 1113-1119
  • the present invention includes a polypeptide capable of binding to HIV gp41 HR1 and inhibiting fusion of HIV cell membrane and host cell cell membrane, an anti-HIV agent comprising the polypeptide as an active ingredient, and the anti-HIV agent.
  • the main object of the present invention is to provide a pharmaceutical composition having the same and a method for treating HIV using the anti-HIV agent.
  • resistance to T20 is considered to be caused by amino acid mutations in the HR1 region and HR2 region of gp41. This is considered to have an effect of reducing the affinity for T20 having inhibitory activity as a partial peptide of the HR2 region.
  • the amino acid mutation in the HR2 region forms an HR2 region having a higher affinity than T20, and is considered to be able to maintain a high affinity for the sequence of the HR1 region after the mutation.
  • Such mutations in the HR1 region and HR2 region can be said to be a purpose for obtaining virus resistance.
  • the present inventors pay attention to the mechanism of acquiring resistance of this virus, and if a membrane fusion inhibitor peptide is designed in accordance with the amino acid sequence of the HR2 region of the T20 resistant strain, high activity against the resistant strain is achieved. It was expected that peptides having high activity against wild type viruses would be found.
  • amino acid mutations in viruses are caused by mutations in DNA bases encoding amino acids, and mutations from specific amino acids are limited to several types of natural amino acids.
  • synthetic chemistry is not limited to mutations in viruses, and it is possible to prepare peptides into which any amino acid is commercially available as a chemical reagent.
  • the present inventors comprehensively synthesized derivatives of HR2 peptides in which the amino acid substitution positions occurring at the contact sites of the HR2 region with the HR1 region were converted to various amino acids, and developed these antiviral products.
  • the membrane fusion inhibitory effect of wild-type strains and HIV-resistant strains, including T20-resistant strains, and host cells was dramatically enhanced.
  • a peptide that binds to N36 including HR1 for example, as described in JP-A-2003-176298, it has a plurality of modular structures consisting of 6 or 7 amino acids, By combining the amino acid at position i and position i + 4 with acidic amino acid and basic amino acid (or vice versa), a salt bridge is formed between the two, making it easier to form an ⁇ -Rix. Things. [0009] With reference to such findings, the present inventors changed the amino acid of T20 to acidic amino acid (X), base
  • one, two or three of the peptides of the present invention obtained in this way are the three HR1 regions of HIV gp41. It is thought to form a complex, inhibit membrane fusion between HIV and the host, and prevent HIV infection.
  • the present invention provides the following polypeptides, anti-HIV agents and pharmaceutical compositions containing the anti-HIV agents.
  • Item 1 A polypeptide containing amino acids in the order shown in Table I below (SEQ ID NO: ⁇ ).
  • x represents serine, alanine, glycine, isoleucine, leucine, methionine, threo.
  • R is an amino acid sequence represented by SEQ ID NO: 4, lj, a variant thereof and a group consisting of an acyl group
  • R represents at least one selected from the group consisting of the amino acid sequence represented by SEQ ID NO: 6, a variant thereof, an amino group and an amino group having a substituent;
  • X is tyrosine
  • X is glutamic acid
  • X is glutamine
  • X is lysine
  • X and X are tryptophan
  • X is alanine
  • X is phenylenolanine
  • X is the same or different and represents a single base mutation from the codon encoding threonine.
  • X is the same or different and is due to a single base mutation from the codon encoding serine.
  • X is the same or different, and eu is due to a single base mutation from the codon encoding leucine.
  • (V) X is the same or different and a single base mutation from the codon encoding isoleucine
  • X is the same or different and is a single base mutation from the codon encoding histidine.
  • X is the same or different and is a single base change from the codon encoding glutamate.
  • At least one force selected from the group consisting of different amino acids, one species;
  • X is the same or different, and a single base mutation from the codon encoding glutamine At least one force selected from the group consisting of amino acids generated by
  • (ix) X is the same or different and is a single base change from the codon encoding asparagine.
  • At least one force selected from the group consisting of different amino acids, one species;
  • (X) X is the same or different and is a single base mutation from the codon encoding lysine.
  • (xi) X is the same or different and is a single base from the codon encoding aspartic acid.
  • (xii) X is the same or different and is a single base change from the codon encoding tryptophan.
  • At least one force selected from the group consisting of different amino acids, one species;
  • (xiii) X is the same or different and is a single base change from the codon encoding tryptophan.
  • (xiv) X is the same or different and represents a single base mutation from the codon encoding alanine.
  • amino acids of B ⁇ IJ, C ⁇ IJ, F column and G column may be substituted according to the following rule (xvi).
  • It is the same or different and is at least one force selected from the group consisting of lysine, arginine, ornithine and histidine, and one basic amino acid.
  • two amino acids in row B and C are basic amino acids
  • two amino acids in row F and G Noic acid is an acidic amino acid
  • amino acids shown in Table I are bound in the following order with R as the N-terminus.
  • 1D-1E-1F-1G is missing from the N-terminal side in order! /, May! / ⁇ ;
  • X is glutamic acid
  • X is alanine
  • Item 2 The polypeptide according to Item 1, wherein X is phenylalanin.
  • Item 3 The polypeptide according to Item 1 or 2, which is either threonine or parin.
  • X is alanine, glycine, isoleucine, leucine, methionine, threonine or
  • Item 4 The polypeptide according to any one of Items 1 to 3, wherein R is a acetyl group and R is - ⁇ .
  • Item 5. A polypeptide containing amino acids in the order shown in Table II below (SEQ ID NO: 2).
  • R represents an amino acid sequence IJ represented by SEQ ID NO: 13, a modified form thereof, and an acyl group.
  • V represents one selected from the group consisting of:
  • R has the amino acid sequence represented by SEQ ID NO: 15, a variant thereof, an amino group, and a substituent.
  • X is alanine
  • X is threonine
  • X is lysine
  • X is glutamic acid
  • X is glutamine
  • X is methionine
  • X is tyrosine
  • X is tryptophan
  • X is phenylenolanine;
  • 1 to 3 amino acids in Table II may be substituted according to the following rules (i) to (xiv).
  • X is the same or different and is a single base change from the codon encoding aspartic acid.
  • At least one force selected from the group consisting of different amino acids, one species;
  • X is the same or different and is due to a single base mutation from the codon encoding alanine.
  • X is the same or different and is a single base change from the codon encoding asparagine.
  • At least one force selected from the group consisting of different amino acids, one species;
  • (V) X is the same or different and is a single base mutation from the codon encoding isoleucine.
  • X is the same or different and is a single base mutation from the codon encoding threonine.
  • X is the same or different and ys is due to a single base mutation from the codon encoding lysine.
  • X is the same or different and is a single base change from the codon encoding glutamate.
  • At least one force selected from the group consisting of different amino acids, one species;
  • (ix) X is the same or different and is a single base mutation from the codon encoding glutamine.
  • (X) X is the same or different and is a single base mutation from the codon encoding methionine
  • (xi) X is the same or different and is a single base mutation from the codon encoding tyrosine.
  • (xii) X is the same or different and is a single base change from the codon encoding tryptophan.
  • At least one force selected from the group consisting of different amino acids, one species;
  • (xiii) X is the same or different and is due to a single base mutation from the codon encoding serine.
  • At least one selected from the group consisting of the resulting amino acids, one species; (xiv) X is the same or different and is a single base from the codon encoding phenylalanin.
  • It is the same or different and is at least one force selected from the group consisting of lysine, arginine, ornithine and histidine, and one basic amino acid.
  • X is alanine
  • X is threonine
  • X is lysine
  • X is glutamic acid
  • X is glutamine
  • X is methionine
  • X is tyrosine
  • X is tryptophan
  • Item 6 The polypeptide according to Item 5, wherein X is phenylenolanine.
  • amino acids in columns B and C are glutamic acid
  • amino acids in columns F and G are lysine
  • Item 7 The polypeptide according to Item 5 or 6, wherein R is a acetyl group, and R is -NH.
  • Item 8 The polypeptide according to any one of Items 1 to 4, which has an amino acid sequence of any one of (a) to (f) below:
  • Item 9 The polypeptide according to any one of Items 1 to 4, having the amino acid sequence of any one of (g) to (v) below.
  • Item 10 The polypeptide according to any one of Items 5 to 7, which has an amino acid sequence of either (w) or (x) below.
  • An anti-HIV agent comprising as an active ingredient the polypeptide according to Item 1 to 10 or!, Or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the anti-HIV agent according to Item 11 together with a pharmaceutically acceptable carrier or additive.
  • Anti-HIV agent according to the polypeptide or claim 11 comprising contained so that a pharmaceutically acceptable 0.01 8 to 10 mg 1 day 1 kg body weight per against salt force adults.
  • Item 14 A method for treating HIV, comprising administering an effective amount of the polypeptide according to any one of Items 1 to 10 to an HIV patient.
  • Item 15 Use of the polypeptide according to claim 10 for producing a composition for treating HIV.
  • the polypeptide of the present invention interacts with HIV gp41 HR1 to inhibit fusion of HIV cell membrane and host cell cell membrane, thereby inhibiting HIV infection.
  • the polypeptide of the present invention can exhibit an excellent anti-HIV activity with a higher affinity for HR1 than T20, which has been conventionally used as an anti-HIV agent.
  • the polypeptide of the present invention can effectively act against HIV, a resistant strain of T20.
  • T20 is known to have anti-HIV activity against HIV-Z, and the polypeptide of the present invention can effectively act on, for example, the HIV-2 strain. Therefore, according to the polypeptide of the present invention, it can be used for the prevention or treatment of HIV infection against a wide variety of HIV.
  • an anti-HIV agent effective for preventing or treating HIV infection
  • a pharmaceutical composition containing the anti-HIV agent comprising such a polypeptide as an active ingredient. be able to.
  • polypeptide of the present invention an anti-HIV agent containing the polypeptide as an active ingredient, and a pharmaceutical composition containing the HIV agent will be described.
  • polypeptide having anti-HIV activity polypeptide having anti-HIV activity
  • the present invention provides polypeptides shown as the following variant I and variant II.
  • variant I a polypeptide that has been modified based on the amino acid sequence of the HR2 region of the HIV-1 NL4-3 strain (SEQ ID NO: 3).
  • variant I is a polypeptide comprising amino acids in the order shown in Table I below.
  • X represents serine, alanine, glycine, isoleucine, leucine, methionine, threo
  • Any one force selected from the group consisting of nin and parin represents one amino acid, preferably serine, alanine, isoleucine, leucine or methionine, more preferably alanine, isoleucine or methionine.
  • amino acids other than X are the following (i) to (xvi)
  • R is an amino acid sequence located at 117-126 of the gp41 HR2 region of HIV-1 (Trp-Met-Glu-
  • Trp-Asp-Arg-Glu-Ile-Asn-Asn SEQ ID NO: 4
  • a variant thereof and a group force consisting of a acyl group. At least one selected force represents one kind.
  • a variant of the amino acid sequence represented by SEQ ID NO: 4 is X -X -X -X -X -X -X-X-X-X-
  • the amino acids corresponding to the B and C columns are dartamic acid, and the amino acids corresponding to the F and G columns are lysine. That is, X -Glu-Glu
  • Met (methionine) of R is an amino acid generated by a single base mutation from a codon encoding methionine, that is, at least selected from the group consisting of leucine, valine, isoleucine, threonine, lysine and arginine. , It is replaced by one or more kinds,
  • Ar of Ar is an amino acid generated by a single base mutation from the codon encoding arginine, that is, leucine, proline, histidine, glutamine, cysteine tryptophan, serine, glycine, isoleucine, methionine, Substituted with at least one selected from the group consisting of threonine and lysine!
  • R is an asinole group
  • the amino terminal N-terminal of the 1D (D column 1st row), 1E, 1F, 1G or 2A amino acid represented in Table I above is Acetyl groups such as acetyl group, propionyl group, butyryl group, benzoyl group, benzyloxycarbonyl group, phthalyl group, honoleminole group, triphenoloacetyl group, benzyl group, etc. may be bonded, preferably acetyl group, propionyl group.
  • R is an amino acid sequence (Asn-Ile-Thr-Asn-Trp-Leu-Trp-Tyr-Ile-Lys: SEQ ID NO: 6) of HIV gp41, a variant thereof, an amino group and It represents at least one force selected from the group consisting of an amino group having a substituent.
  • amino acid sequence variant represented by SEQ ID NO: 6 is X -X -X -X -X -X -X-X-X-X-
  • Examples thereof include a variant represented by X 1 -X 2 -X, in which an amino acid is substituted according to the following rule (1) to (xvi).
  • the amino acids corresponding to the B and C columns are dartamic acid
  • the amino acids corresponding to the F and G columns are lysine. That is, X -Lys-Lys
  • An amino group such as -NH, methylamino group, dimethylamino group, ethylamino group, jetylamino group, benzylamino group or the like may be bonded to the C-terminal carbonyl group of -NH, methylamino group, dimethylamino group, An ethylamino group or a jetylamino group is bonded, and more preferably —NH is bonded.
  • R is a acetyl group and R is —NH.
  • amino acids are defined as follows.
  • X is glutamic acid
  • X is glutamine
  • X is lysine
  • X and X are tryptophan
  • X is alanine
  • X is phenylenolanine
  • X is the same or different and is a single base mutation from the codon encoding threonine.
  • the resulting amino acid is at least one selected from the group consisting of isoleucine, methynin, asparagine, lysine, serine, arginine, proline and alanine.
  • X is the same or different, and is caused by a single base mutation from the codon encoding serine.
  • Resulting amino acids such as phenylalanine, leucine, tyrosine, cysteine, tryptophan, proline, thread nin, alanine, isoleucine, asparagine, anoleginin, glycine At least one force selected from the group consisting of thin and cysteine.
  • X is the same or different and is due to a single base mutation from the codon encoding leucine.
  • (V) X is the same or different and is a single base mutation from the codon encoding isoleucine
  • X is the same or different and is a single-base mutation from the codon encoding histidine.
  • X is the same or different and is a single-base mutation from the codon encoding glutamine
  • X is the same or different, and is a single base change from the codon encoding asparagine.
  • (X) X may be the same or different. At least one selected from the group consisting of different amino acids, ie, isoleucine, threonine, serine, tyrosine, histidine, lysine and aspartic acid. Due to a single base mutation from the codon encoding lysine.
  • X is the same or different and is a single base from the codon encoding aspartic acid. It is at least one selected from the group consisting of amino acids generated by mutation, ie, valine, alanine, glycine, tyrosine, histidine, glutamic acid, and asparagine.
  • X is the same or different and is a single base change from the codon encoding tryptophan.
  • It is at least one selected from the group consisting of different amino acids, namely leucine, serine, arginine, cysteine and dalysin.
  • X is the same or different and is one from the codons encoding alanine and tryptophan.
  • X is the same or different and represents a single-base mutation from the codon encoding alanine.
  • the resulting amino acid is at least one selected from the group consisting of valine, aspartic acid, glutamic acid, glycine, serine, proline and threonine.
  • (XV) X is the same or different from the codons encoding alanine and phenylalanin.
  • amino acids of B ⁇ IJ, C ⁇ IJ, F column and G column may be substituted according to the following rule (xvi).
  • the two amino acids in columns B and C are basic amino acids
  • the two amino acids in columns F and G are acidic amino acids. [0053] That is, assuming that the acidic amino acid is X and the basicity is X, for example, 7 amino acids in the second row
  • the acid sequences are (A) ⁇ — ⁇ —X — ⁇ — ⁇ — ⁇ — in the order 2A-2B-2C-2D-2E-2F-2G
  • amino acid sequence IJ located in the 2nd to 4th rows can be obtained by combining the amino acid sequences combined in the order shown in (a) and ( ⁇ ).
  • ( ⁇ ) and (/ 3) can be arbitrarily combined and used, for example, ( ⁇ )-)-)-); 3) — (/ 3
  • the acidic amino acid is preferably glutamic acid, aspartic acid, cystic acid or the like, more preferably glutamic acid or aspartic acid, and still more preferably glutamic acid.
  • the basic amino acid is preferably lysine, arginine, ornithine or histidine, more preferably lysine, arginine or ornithine, more preferably lysine or arginine, and still more preferably. Lysine.
  • 1D-1E-1F-1G may lack the N-terminal side force. That is, X -X
  • amino acids represented as x -x -x -x (SEQ ID NO: 10) are respectively
  • polypeptide of the present invention has the following amino acids (a) to (u) in the amino acid sequence shown in Table I: Those with the amino acid sequence shown are preferred
  • X is glutamic acid
  • X is glutamine
  • X is alanine
  • X is phenylenolanine
  • X is glutamic acid
  • X is glutamine
  • X is aspartic acid, X and X force S tryptophan,
  • X is alanine
  • X is phenylenolanine
  • R is an acetyleno group and R is NH.
  • X is glutamic acid
  • X is alanine
  • X is phenylenolanine
  • X is serine, alanine, glycine, isoleucine, leucine, methionine, thread nin and
  • R is an acetylenic group, and R is NH.
  • the present invention also provides the following polypeptide as variant II, which is modified based on the amino acid sequence (SEQ ID NO: 12) of the HR2 region of HIV-2 EHO strain. That is, the variant ⁇ is a polypeptide containing amino acids in the order represented by the following ⁇ (SEQ ID NO: 2).
  • R is an amino acid sequence in the gp41 HR2 region of HIV-2 IjTrp-Gln-Gln-Trp-Glu-Arg-Gln-V
  • a variant of the amino acid sequence represented by SEQ ID NO: 13 is X -X -X -X -X -X -X -X -X
  • Trp uin uln Trp Glu Arg uin
  • the amino acids corresponding to the B and C columns are dartamic acid, and the amino acids corresponding to the F and G columns are lysine. That is, X -Glu-Glu
  • R Arg (arginine) is a single base mutation from the codon encoding arginine.
  • R is an acyl group
  • 1D D column 1st row
  • 1E, 1F, 1G represented in Table I above
  • the N-terminal amino group of the amino acid at position 2A is an acyl group such as acetyl group, propionyl group, butyryl group, benzoyl group, benzyloxycarbonyl group, phthalyl group, formyl group, trifanoloacetyl group, benzyl group, etc. May be bonded to each other, preferably a acetyl group, a propionyl group, a butyryl group, a benzoyl group, a phthalinole group, a honoreminore group, or a trifnoreo acetyl group, more preferably a acetyl group.
  • acyl group such as acetyl group, propionyl group, butyryl group, benzoyl group, benzyloxycarbonyl group, phthalyl group, formyl group, trifanoloacetyl group, benzyl group, etc. May be bonded to each other
  • R is the amino acid sequence in gp41 of HIV-2 Asp- Phe- Thr- Ser- Trp- Met- Ala- Tyr- lie- Arg
  • SEQ ID NO: 15 a variant thereof, at least one selected from the group consisting of an amino group and an amino group having a substituent, and one kind.
  • a variant of the amino acid sequence represented by SEQ ID NO: 15 is X -X -X -X -X -X -X -X -X -X
  • the amino acids corresponding to the B and C columns are dartamic acid, and the amino acids corresponding to the F and G columns are lysine. That is, X -Lys-Lys
  • R is an amino group or an amino group having a substituent
  • An amino group such as an amino group, an ethylamino group, a jetylamino group, or a benzylamino group may be bonded, preferably -NH, a methylamino group, a dimethylamino group, an ethylamino group, or a jetamino group, more preferably -NH. Join.
  • R is a acetyl group and R is —NH.
  • X is alanine
  • X is lysine
  • X is glutamic acid
  • X is glutamine
  • X is methionine
  • X is phenylenolanine
  • X is the same or different and is generated from a single base change from a codon encoding an acid, ie, a group consisting of valine, alanine, glycine, tyrosine, histidine, glutamic acid, and asparagine. At least one power selected, one kind
  • X is the same or different and is due to a single base mutation from the codon encoding alanine.
  • valine at least one selected from the group consisting of valine, aspartic acid, glutamic acid, glycine, serine, proline and threonine.
  • X is the same or different and is a single base change from the codon encoding asparagine.
  • One amino acid generated by different species that is, at least one selected from the group consisting of isoleucine, threonine, serine, tyrosine, histidine, lysine and aspartic acid.
  • (V) X is the same or different and is a single base mutation from the codon encoding isoleucine.
  • X is the same or different and is a single base mutation from a codon encoding threonine
  • X is the same or different and is a single base change from the codon encoding glutamic acid.
  • X is the same or different and is a single base mutation from the codon encoding glutamine.
  • the resulting amino acid is at least one selected from the group consisting of leucine, proline, anoleginine, lysine, histidine and glutamic acid.
  • X is the same or different and is a single base mutation from the codon encoding methionine
  • X is the same or different and represents a single base mutation from the codon encoding tyrosine.
  • the resulting amino acid ie, at least one selected from the group consisting of phenylalanine, serine, cystine, histidine, asnoragin and aspartic acid is one.
  • X is the same or different and represents a single base change from the codon encoding tryptophan.
  • It is at least one selected from the group consisting of different amino acids, namely leucine, serine, arginine, cysteine and dalysin.
  • X is the same or different and is due to a single base mutation from the codon encoding serine.
  • the resulting amino acids phenylalanine, leucine, tyrosine, cysteine, tryptophan, proline, thread nin, alanine, isoleucine, wasparagine, anoleginine, glycine At least one force selected from the group consisting of thin and cysteine.
  • X is the same or different and is a single base from the codon encoding phenylalanin.
  • amino acids of B ⁇ IJ, C ⁇ IJ, F row and G row may be substituted by the law of (XV).
  • (XV) is defined in the same manner as (xvi) in Table I above.
  • amino acids shown in Table II are the same as in Table I above, with R as the N-terminus and R as the C-terminus.
  • 1D-1E-1F-1G is defined in the same way as in Table I.
  • the amino acid used in the above-mentioned variant I and variant II of the present invention is preferably L-form (Lamino acid), but D-form may also be used. When using D-form, it is preferable to convert all optically active amino acids into D-form.
  • the polypeptide of the present invention preferably has any one of the following amino acid sequences (a) to (x).
  • (a) to (v) correspond to variant I
  • (w) and (X) correspond to variant II.
  • the polypeptide of the present invention has the following amino acid sequences (g) to (n).
  • the polypeptide of the present invention can form a stable ⁇ _helix structure when the N-terminus is acetylated and the C-terminus is amidated.
  • the heel end and the C terminus are not bonded to each other and are preferably acyclic.
  • the polypeptide of the present invention can be produced by a known polypeptide synthesis method, particularly a liquid phase synthesis method or a solid phase synthesis method.
  • a known polypeptide synthesis method particularly a liquid phase synthesis method or a solid phase synthesis method.
  • synthesize DN by encoding the polypeptide of the present invention into a host cell by gene recombination technique and expressing it.
  • N-protected amino acid in which the amino group of the amino acid most corresponding to the C-terminus is protected with a urethane-type protecting group such as 9-fluorenylenomethyloxycarbonyl (Fmoc) group is used.
  • Fmoc 9-fluorenylenomethyloxycarbonyl
  • the protecting group of the amino group After binding the carboxyl group to an insoluble resin having an amino group, the protecting group of the amino group is removed, the protected amino acid is condensed sequentially in the N-terminal direction, and then the protecting group of the insoluble resin and amino acid is deprotected.
  • the polypeptide of the present invention can be obtained.
  • the insoluble resin having an amino group is not particularly limited, but Fmoc-NH-SA L resin (4_ (2 ', 4'-dimethoxyphenyl-Fmoc-aminoethyl) phenoxy linker resin) is preferable.
  • the target can be given directly by cleavage.
  • the protected amino acid used for the synthesis of the polypeptide of the present invention can be obtained by protecting a functional group with a known protecting group by a known method, or by using a commercially available protected amino acid. .
  • a protecting group use the power of publicity.
  • a known method such as DIPCDI (diisopropylcarposimide) -HOBt (l_hydroxybenzotriazole) method can be used.
  • This condensation reaction can be carried out in a known solvent, and examples thereof include organic solvents such as dimethylformamide.
  • the reagent for removing the protecting group of the amino group is not limited, and the protecting group such as the Fmoc group can be cleaved by a known reagent such as piperidine / dimethylformamide.
  • a protected polypeptide having a desired amino acid sequence can be obtained.
  • Fmoc-NH-SAL resin is used as an insoluble resin, the resin and protecting group can be removed simultaneously by treating with TMSBr (trimethylsilyl bromide), TFA (trifluoroacetic acid), etc. Monkey.
  • polypeptide of the present invention thus obtained can be obtained by publicly known methods such as extraction, recrystallization, various chromatographies (gel filtration, ion exchange, distribution, adsorption), electrophoresis, countercurrent distribution and the like. It can be isolated and purified by means, and a method using reverse phase high performance liquid chromatography is preferred.
  • the polypeptide of the present invention can prevent HIV from invading (infecting) a host cell (eg, T cell) in a living body, or the infected HIV can proliferate in the host cell and further increase.
  • a host cell eg, T cell
  • the polypeptides of the present invention also include pharmaceutically acceptable salts thereof.
  • the strength and the salt include non-toxic alkali metal salts such as sodium, potassium, lithium, strength, magnesium, and alkaline earth metal salts prepared by methods well known in the art.
  • the above salts include non-toxic acid addition salts obtained by reacting the polypeptide of the present invention with a suitable organic acid or inorganic acid.
  • Typical acid addition salts include, for example, hydrochloride, hydrobromide, sulfate, acetate, valerate, laurate, lactate, phosphate, p-toluenesulfonate (tosylate), Examples include citrate, maleate, fumarate, succinate, tartrate, glycolate, benzenesulfonate and methanesulfonate. These salts can be used alone or in combination of two or more.
  • polypeptide of the present invention or a pharmaceutically acceptable salt thereof is each independently an active ingredient, or the polypeptide of the present invention and one or more of its salts are combined as an active ingredient. It can also be used as an anti-HIV agent.
  • conventionally known additives such as isotonic agents, inorganic salts, buffers, solubilizers, chelating agents, antioxidants, fragrances, preservatives, and pH adjusters may be added to the above polypeptides.
  • V in a range, combining in a range, It can also be used as the anti-HIV agent of the present invention.
  • the present invention comprises the above-mentioned anti-HIV agent as an active ingredient, together with a conventionally known pharmaceutically acceptable carrier or various additives (excipient, diluent, binder, disintegrant, etc.).
  • a pharmaceutical composition having anti-HIV activity is also provided.
  • compositions can be selected depending on the purpose of treatment, and representative examples thereof include tablets, pills, powders, solutions, suspensions, capsules, sustained release.
  • Liquid preparations for oral or parenteral administration such as solid preparations such as microcapsules and injections (solutions, suspensions, etc.).
  • the above-mentioned preparation carrier is shaped like lactose, sucrose, sodium chloride, dextrose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, key acid, potassium phosphate, etc.
  • the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, film-coated tablets, double tablets or multilayer tablets.
  • excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc; gum arabic powder, tragacanth powder, gelatin, ethanol, etc.
  • disintegrants such as laminaran and agar can be used.
  • Capsules are prepared according to conventional methods V, and various preparations exemplified above for the active ingredients of the present invention. It is prepared by mixing with a carrier and filling hard gelatin capsules, soft capsules, and the like.
  • composition of the present invention is prepared as a liquid preparation for oral administration, a pharmaceutically acceptable solution, emulsion, suspension or syrup containing a conventional inert diluent such as water. , Elixirs and the like, and further auxiliary agents such as wetting agents, emulsions, suspensions and the like can be added, and these are prepared according to a conventional method.
  • a pharmaceutically acceptable solution, emulsion, suspension or syrup containing a conventional inert diluent such as water.
  • Elixirs and the like, and further auxiliary agents such as wetting agents, emulsions, suspensions and the like can be added, and these are prepared according to a conventional method.
  • the pharmaceutical composition of the present invention is prepared as a liquid preparation for parenteral administration, diluents such as water, ethyl alcohol, propylene glycol, polyethylene glycol, ethoxyethylene sorbitan fatty acid esters and vegetable oils such as olive oil, etc. And injectable organic esters such as ethyl oleate. Furthermore, usual solubilizers, buffers, wetting agents, emulsifiers, suspending agents, preservatives, dispersing agents and the like can be added to these. Sterilization can be performed by, for example, filtration operation through a bacteria retention filter, blending of a bactericide, irradiation treatment, and heat treatment. They can also be prepared in the form of sterile solid compositions that can be dissolved in sterile water or a suitable sterilizable medium immediately before use.
  • diluents such as water, ethyl alcohol, propylene glycol, polyethylene glycol, ethoxyethylene sorbitan fatty
  • the pharmaceutical composition of the present invention is prepared in the form of a liquid preparation, it is lyophilized to a state that can be stored, and then dissolved in a buffer solution containing water for use, saline, etc. It can also be used after adjusting to an appropriate concentration.
  • the pharmaceutical composition of the present invention includes various components that can be used in ordinary protein preparations, such as stabilizers, bactericides, buffers, isotonic agents, chelating agents, pH adjusters, A surfactant, phospholipid, and the like can be used as appropriate.
  • the pharmaceutical composition of the present invention may contain a colorant, a preservative, a fragrance, a flavoring agent, a sweetening agent, and other pharmaceuticals as necessary.
  • the administration method of the anti-HIV agent or the pharmaceutical composition having anti-HIV activity of the present invention is determined according to various preparation forms, the degree of disease, etc., which are not particularly limited. For example, tablets, pills, liquids, suspensions, emulsions, granules, and capsules are administered orally, and injections are administered alone or mixed intravenously with normal fluids such as glucose or amino acids. If necessary, it can be administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally.
  • the dosage of the above pharmaceutical composition is not particularly limited, and is appropriately selected depending on the desired therapeutic effect, administration method, treatment period, age of livestock, etc.
  • the effective component amount is about 0.01 g to 10 mg, preferably about 0.1 ⁇ gl mg, more preferably about 0.01 mg to l mg, more preferably about 0.1 mg to l mg per kg of body weight per day.
  • the preparation can be administered once or several times a day.
  • the polypeptide of the present invention in the prevention or treatment of HIV infection or the treatment of human AIDS, is, for example, currently practiced in the clinical field. It can also be used in combination with other known therapies such as HAART (Highly Active Anti-retroviral Therapy).
  • HAART Highly Active Anti-retroviral Therapy
  • anti-HIV activity was measured for the polypeptides comprising the sequences (a) to (o) described above by MAGI assay.
  • Anti-HIV activity against T20 resistant virus was evaluated using T20 and the polypeptides (a) to (d) and (g) to (n).
  • Anti-HIV activity was evaluated by the same test method as in (2) above, except that the T20 resistant strain virus was used instead of the virus HIV-red clone NL4-3.
  • T20 resistant viruses In clinical strains exhibiting T20 resistance, mutations such as gp41 V38A and N43D are observed. However, since these T20 resistant viruses have poor growth ability, they were prepared as viruses that can be applied to Atsei by introducing mutations in some sequences (substitution of aspartate at position 36 with glycine). Is described as DG). That is, in this study, the activity value against DG was defined as the activity value against wild type HIV, and the tendency of anti-HIV activity was evaluated using DG / V38A and DG / N43D as viruses corresponding to the mutant strain (T20 resistant strain).
  • DG / V38A is a resistant strain in which palin at position 38 in the HR1 region of gp41 of T20 resistant HIV is mutated to alanine.
  • DG / N43D is a resistant strain in which asparagine at position 43 in the HR1 region of gp41 of T20 resistant HIV is mutated to aspartic acid.
  • polypeptide of the present invention also showed excellent antiviral activity against T20 resistant strains of HIV.
  • Anti-HIV activity against HIV-2 virus was evaluated using T20 and the polypeptides (g), (w) and (X).
  • Anti-HIV activity was evaluated by the same test method as in (2) above, except that HIV-2 EHO strain virus was used instead of virus HIV-red clone NL4-3. The results are shown in Table G below.
  • the polypeptide of the present invention showed excellent antiviral activity against HIV-2 (EHO).
  • the polypeptides (g) and (w) exhibited excellent antiviral activity against HIV-1 and also exhibited excellent antiviral activity against HIV-2.
  • SEQ ID NO: 1 represents the amino acid sequence shown in Table I.
  • SEQ ID NO: 2 represents the amino acid sequence shown in Table II.
  • SEQ ID NO: 5 represents the amino acid sequence of a variant of HIV-1 (NL4-3) gp41 HR2 region 117-126.
  • SEQ ID NO: 7 represents the amino acid sequence of a variant of HIV-1 (NL4-3) gp41 HR2 region 163-173.
  • SEQ ID NO: 8 represents the amino acid sequence of ( ⁇ ).
  • SEQ ID NO: 9 represents the amino acid sequence of ( ⁇ ).
  • SEQ ID NO: 10 represents the amino acid sequence of 1D-1E-1F-1G in Table I
  • SEQ ID NO: 11 represents the amino acid sequence of 1E-1F-1G in Table I
  • SEQ ID NO: 14 represents the amino acid sequence of a variant of the partial sequence of HIV-2 (EHO) gp41 HR2 region.
  • SEQ ID NO: 16 represents the amino acid sequence of a variant of the partial sequence of HIV-2 (EHO) gp41.
  • SEQ ID NO: 17 represents the amino acid sequence of (a) T20 / S138A.
  • SEQ ID NO: 18 represents the amino acid sequence of (b) T20 / S138I.
  • SEQ ID NO: 19 represents the amino acid sequence of (c) T20 / S138L.
  • SEQ ID NO: 20 represents the amino acid sequence of (d) T20 / S138M.
  • SEQ ID NO: 21 represents the amino acid sequence of (e) T20 / S138T.
  • SEQ ID NO: 22 represents the amino acid sequence of (f) T20 / S138V.
  • SEQ ID NO: 23 represents the amino acid sequence of (g) T20EK.
  • SEQ ID NO: 24 represents the amino acid sequence of (h) T20EK / S138A.
  • SEQ ID NO: 25 represents the amino acid sequence of (i) T20EK / S138G.
  • SEQ ID NO: 26 represents the amino acid sequence of (j) T20EK / S138I.
  • SEQ ID NO: 27 represents the amino acid sequence of (k) T20EK / S138L.
  • SEQ ID NO: 28 represents the amino acid sequence of (DT20EK / S138M.
  • SEQ ID NO: 29 represents the amino acid sequence of (m) T20EK / S138T.
  • SEQ ID NO: 30 represents the amino acid sequence of (n) T20EK / S138V. No.
  • 31 represents the amino acid sequence of (o) T20EK32 SEQ ID NO: 32 represents the amino acid sequence of (p) T20EK / W155A SEQ ID NO: 33 represents the amino acid sequence of (q) T20EK / W161A SEQ ID NO: 34 (R) represents the amino acid sequence of T20EK / F162A SEQ ID NO: 35 represents the amino acid sequence of (s) T20EK-b.
  • SEQ ID NO: 36 represents the amino acid sequence of (t) T20EK-d.
  • SEQ ID NO: 37 represents the amino acid sequence of (u) T20EK-g.
  • SEQ ID NO: 38 represents the amino acid sequence of (v) T20EK-h.
  • SEQ ID NO: 39 represents the amino acid sequence of (w) T20 / HIV_2.
  • SEQ ID NO: 40 represents the amino acid sequence of (x) T20EK / HIV-2.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Microbiology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • AIDS & HIV (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne : un polypeptide ayant une excellente activité anti-VIH, qui est obtenu en modifiant une séquence d'acides aminés correspondant à la région HR2 du VIH ; un agent anti-VIH comprenant le polypeptide comme ingrédient actif ; une composition pharmaceutique comprenant l'agent anti-VIH ; un procédé pour traiter le VIH à l'aide de l'agent anti-VIH ; et autres.
PCT/JP2007/070807 2006-10-25 2007-10-25 Agent anti-vih WO2008050830A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2008541019A JPWO2008050830A1 (ja) 2006-10-25 2007-10-25 抗ｈｉｖ剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006290241 2006-10-25
JP2006-290241 2006-10-25

Publications (1)

Publication Number Publication Date
WO2008050830A1 true WO2008050830A1 (fr) 2008-05-02

Family

ID=39324615

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2007/070807 WO2008050830A1 (fr) 2006-10-25 2007-10-25 Agent anti-vih

Country Status (2)

Country Link
JP (1) JPWO2008050830A1 (fr)
WO (1) WO2008050830A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20200002923A (ko) * 2017-04-18 2020-01-08 인스티튜트 오브 패쏘젠 바이올로지, 차이니즈 아카데미 오브 메디컬 사이언시스 Hiv를 강력하게 저해하는 리포펩티드, 그의 유도체, 그의 약학적 조성물 및 그의 용도
WO2022101193A1 (fr) * 2020-11-10 2022-05-19 Fundació Hospital Universitari Vall D'hebron - Institut De Recerca Peptides de pénétration cellulaire

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08511525A (ja) * 1993-06-07 1996-12-03 ドューク ユニバーシティー Ｈｉｖ伝播の合成ペプチド抑制物質
JP2003176298A (ja) * 2001-09-27 2003-06-24 Kansai Tlo Kk 抗ｈｉｖ剤
WO2006025536A1 (fr) * 2004-09-02 2006-03-09 Kyoto University Agent anti-virus du sras

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08511525A (ja) * 1993-06-07 1996-12-03 ドューク ユニバーシティー Ｈｉｖ伝播の合成ペプチド抑制物質
JP2003176298A (ja) * 2001-09-27 2003-06-24 Kansai Tlo Kk 抗ｈｉｖ剤
WO2006025536A1 (fr) * 2004-09-02 2006-03-09 Kyoto University Agent anti-virus du sras

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] POZNIAK A. ET AL.: "HIV fusion inhibitors", accession no. STN Database accession no. (136:384476) *
J. HIV THER., vol. 6, 2001, pages 91 - 94 *
REY-CUILLE M.A. ET AL.: "HIV-2 EHO isolate has a divergent envelope gene and induces single cell killing by apoptosis", VIROLOGY, vol. 202, 1994, pages 471 - 476, XP001020307, DOI: doi:10.1006/viro.1994.1364 *
XU L. ET AL.: "Emergence and evolution of enfuvirtide resistance following long-term therapy involves heptad repeat 2 mutations within gp41", ANTIMICROB. AGENTS CHEMOTHER., vol. 49, 2005, pages 1113 - 1119, XP055168694, DOI: doi:10.1128/AAC.49.3.1113-1119.2005 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20200002923A (ko) * 2017-04-18 2020-01-08 인스티튜트 오브 패쏘젠 바이올로지, 차이니즈 아카데미 오브 메디컬 사이언시스 Hiv를 강력하게 저해하는 리포펩티드, 그의 유도체, 그의 약학적 조성물 및 그의 용도
JP2020517741A (ja) * 2017-04-18 2020-06-18 インスティテュート オブ パソジェン バイオロジー，チャイニーズ アカデミー オブ メディカル サイエンシズ Ｈｉｖを強力に阻害するためのリポペプチド、その誘導体、その医薬組成物及びその使用
JP7057822B2 (ja) 2017-04-18 2022-04-20 インスティテュート オブ パソジェン バイオロジー，チャイニーズ アカデミー オブ メディカル サイエンシズ Ｈｉｖを強力に阻害するためのリポペプチド、その誘導体、その医薬組成物及びその使用
KR102389792B1 (ko) 2017-04-18 2022-04-22 인스티튜트 오브 패쏘젠 바이올로지, 차이니즈 아카데미 오브 메디컬 사이언시스 Hiv를 강력하게 저해하는 리포펩티드, 그의 유도체, 그의 약학적 조성물 및 그의 용도
US11680086B2 (en) 2017-04-18 2023-06-20 Shanxi Kangbao Biological Product Co., Ltd. Lipopeptide for potently inhibiting HIV, derivative thereof, pharmaceutical composition thereof and use thereof
WO2022101193A1 (fr) * 2020-11-10 2022-05-19 Fundació Hospital Universitari Vall D'hebron - Institut De Recerca Peptides de pénétration cellulaire

Also Published As

Publication number Publication date
JPWO2008050830A1 (ja) 2010-02-25

Similar Documents

Publication Publication Date Title
JP3266311B2 (ja) 新規ポリペプチドおよびこれを用いる抗ｈｉｖ剤
JP4006021B2 (ja) ケモカインの生物学的活性の強化法
JPH08511784A (ja) エイズを撲滅する医薬品を製造するためのノナペプチドおよびデカペプチドの使用
JP4812347B2 (ja) 抗菌性ペプチド
US7745390B2 (en) Antimicrobial peptides
JP3178835B2 (ja) 新規ポリペプチドおよびこれを用いる抗ｈｉｖ剤
CN102336815A (zh) 病毒感染的治疗
WO2002020561A1 (fr) Nouveaux polypeptides et medicaments anti-vih contenant lesdits polypeptides
WO2006025536A1 (fr) Agent anti-virus du sras
JP2020519623A (ja) メトトレキサートとペプチドの結合体
WO2008050830A1 (fr) Agent anti-vih
CN115724919A (zh) 强效抑制艾滋病病毒及其耐药毒株的新型膜融合抑制剂及其药物用途
WO2000027880A2 (fr) Peptides derives de rantes a activite anti-vih
JPH0625288A (ja) ペプチドまたはその塩
US20200071357A1 (en) Antimicrobial peptides
JP4332618B2 (ja) 抗ｈｉｖ剤
KR950703357A (ko) 레트로바이러스 감염의 억제방법(inhibtion of retrovirus infection)
PT99791B (pt) Processo para a preparacao de peptidos seleccionados do antigene especifico de grupo (gas) do virus da imunodeficiencia humana (hiv) e de composicoes farmaceu-ticas que os contem
JPH03120225A (ja) 新規ペプチドおよびこれを含有する降圧剤
JP3726106B2 (ja) アンジオテンシン変換酵素阻害剤及び血圧降下剤
JPH03284694A (ja) 新規トリペプチド及び血圧降下剤
JP3232675B2 (ja) 新規ペプチドおよび抗菌剤
JP2002080494A (ja) 新規な抗脱毛ペプチド
JP2008063275A (ja) 抗ｆｉｖ剤
JPH0656889A (ja) 新規ペプチドおよび抗菌剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07830541

Country of ref document: EP

Kind code of ref document: A1

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2008541019

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07830541

Country of ref document: EP

Kind code of ref document: A1

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)