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WO1995019370A1 - Peptides amphiphiliques formant des canaux ioniques et presentant des modifications n-terminales - Google Patents

Peptides amphiphiliques formant des canaux ioniques et presentant des modifications n-terminales Download PDF

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Publication number
WO1995019370A1
WO1995019370A1 PCT/US1995/000714 US9500714W WO9519370A1 WO 1995019370 A1 WO1995019370 A1 WO 1995019370A1 US 9500714 W US9500714 W US 9500714W WO 9519370 A1 WO9519370 A1 WO 9519370A1
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WO
WIPO (PCT)
Prior art keywords
peptide
amino acid
lys
basic
seq
Prior art date
Application number
PCT/US1995/000714
Other languages
English (en)
Inventor
U. Prasad Kari
Taffy J. Williams
Michael Mclane
Original Assignee
Magainin Pharmaceuticals Inc.
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 Pharmaceuticals Inc. filed Critical Magainin Pharmaceuticals Inc.
Priority to JP7519212A priority Critical patent/JPH09507669A/ja
Priority to EP95909267A priority patent/EP0750632A1/fr
Priority to AU17288/95A priority patent/AU693518B2/en
Publication of WO1995019370A1 publication Critical patent/WO1995019370A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/463—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from amphibians
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to biologically active peptides . More particularly, this invention relates to biologically active peptides having N-terminal (or amino-terminal )
  • the peptide or protein is preferably an ion
  • T is a lipophilic moiety
  • W is T or hydrogen
  • lipophilic means that the lipophilic moiety enhances the interaction of the peptide or protein with a lipid membrane, such as, for example, a cell membrane .
  • Lipophilic moieties which may be employed, include, but are not limited to, any moiety which may be placed on the N-terminal of the peptide through a condensation reaction with nitrogen.
  • the lipophilic moiety T may be, for example, a carboxylic acid, a phosphoric acid, preferably an
  • alkylphosphoric acid a phosphonic acid, preferably an alkylphosphonic acid, a sulfonic acid, preferably an
  • T is: , wherein R is a hydrocarbon having at least two and no more than 16 carbon atoms.
  • R is an alkyl group.
  • the alkyl group may be a straight chain or branched chain alkyl group; or a cycldalkyl group.
  • R may be CH 3 (CH 2 ) n -, wherein n is from 1 to 14.
  • n is from 3 to 12, more preferably from 4 to 11, still more preferably from 6 to 11, and most preferably n is 6, whereby T is an octanoyl group.
  • R is an aromatic (including phenyl and naphthyl), or an alkyl aromatic group.
  • R may be O-(CH 2 ) z -, wherein z is from 0 to 6.
  • R is
  • n is from 1 to 5.
  • n is 1, whereby R is an ibuprofyl group.
  • T is: wherein x is from 1 to 14.
  • x is 2, and T is a succinyl group.
  • T is:
  • y is from 1 to 14.
  • y is 12, whereby T is a sphingosine group.
  • T is: , wherein x and y are hereinabove described.
  • x is 2, and y is 12.
  • W is hydrogen
  • the biologically active peptides or proteins of the present invention are preferably ion channel-forming peptides.
  • An ion channel-forming peptide or protein or ionophore is a peptide or protein which increases the permeability for ions across a natural or synthetic lipid membrane.
  • pgs. 5072-5076 (July 1988) describes methodology which indicates whether or not a peptide or protein has ion
  • channel-forming protein is a peptide or protein which has ion channel-forming properties as determined by the method of Christensen, et al.
  • An amphophilic peptide or protein is a peptide or protein which includes both hydrophobic and hydrophilic peptide or protein regions.
  • the ion channel-forming peptides employed in the present invention are generally water soluble to a concentration of at least 20 mg/ml at neutral pH in water.
  • the structure of such peptide provides for flexibility of the peptide molecule.
  • Such peptides are capable of forming an alpha-helical structure. When the peptide is placed in water, it does not assume an amphophilic structure. When the peptide encounters an oily surface or membrane, the peptide chain folds upon itself into a rodlike structure.
  • peptides have at least 7 amino acids, and in many cases have at least 20 amino acids. In most cases, such peptides do not have in excess of 40 amino acids.
  • the peptides and/or analogues or derivatives thereof may be administered to a host; for example a human or non-human animal, in am amount effective to inhibit growth of a target cell, virus, or virally-infected cell.
  • the peptides and/or analogues or derivatives thereof may be used as antimicrobial agents, anti-viral agents, anti-bacterial agents, anti-tumor agents, anti-parasitic agents, spermicides, as well as exhibiting other bioactive functions.
  • antimicrobial means that the polypeptides or proteins of the present invention inhibit, prevent, or destroy the growth or proliferation of microbes such as bacteria, fungi, viruses, or the like.
  • anti-bacterial means that the peptides or proteins employed in the present invention produce effects adverse to the normal biological functions of bacteria, including death or destruction and prevention of the growth or proliferation of the bacteria when contacted with the peptides or proteins.
  • antibiotic means that the peptides or proteins employed in the present invention produce effects adverse to the normal biological functions of the non-host cell, tissue or organism, including death or destruction and prevention of the growth or proliferation of the non-host cell, tissue, or organism when contacted with the peptides or proteins.
  • spermicidal as used herein means that the peptides or proteins employed in the present invention, inhibit, prevent, or destroy the motility of sperm.
  • anti-fungal means that the peptides or proteins employed in the present invention inhibit, prevent, or destroy the growth or proliferation of fungi.
  • anti-viral means that the peptides or proteins employed in the present invention inhibit, prevent, or destroy the growth or proliferation of viruses, or of virally-infected cells.
  • anti-tumor means that the peptides or proteins inhibits the growth of or destroys tumors, including cancerous tumors.
  • anti-parasitic means that the peptides or proteins employed in the present invention inhibit, prevent, or destroy the growth or proliferation of parasites.
  • the peptides or proteins of the present invention have a broad range of potent antibiotic activity against a plurality of microorganisms including gram-positive and gram-negative bacteria, fungi, protozoa, and the like, as well as
  • the peptides or proteins of the present invention allow a method for treating or controlling microbial infections
  • Such treatment may comprise
  • administering to a host organism or tissue susceptible to or affiliated with a microbial infection an antimicrobial amount of at least one of the peptides or proteins.
  • antibiotics because of the antibiotic, antimicrobial, antiviral, and antibacterial properties of the peptides or proteins, they may also be used as preservatives or sterilants or
  • the peptides or proteins and/or derivatives or analrgues thereof may be administered in combination with a non-toxic pharmaceutical carrier or vehicle such as a filler, non- toxic buffer, or physiological saline solution.
  • a non-toxic pharmaceutical carrier or vehicle such as a filler, non- toxic buffer, or physiological saline solution.
  • compositions may be used topically or
  • peptide or protein compositions may also be used in combination with adjuvants, protease inhibitors, or compatible drugs where such a combination is seen to be desirable or advantageous in controlling infection caused by harmful microorganisms including protozoa, viruses, and the like, as well as by parasites .
  • the peptides or proteins of the present invention may be administered to a host; in particular a human or non-human animal, in an effective antibiotic and/or anti-tumor and/or anti-fungal and/or anti-viral and/or anti-microbial and/or antibacterial and/or anti-parasitic and/or spermicidal amount.
  • composition in accordance with the invention will contain an effective anti-microbial amount and/or an effective spermicidal amount and/or an effective anti-fungal amount and/or an effective anti-viral amount and/ or an effective anti-tumor amount and/or an effective
  • peptides or proteins of the present invention which have such activity.
  • the peptides or proteins may be administered by direct application of the peptides or
  • proteins to the target cell or virus or virally-infected cell or indirectly applied through systemic administration.
  • the peptides or proteins of the present invention may also be employed in promoting or stimulating healing of a wound in a host.
  • wound healing includes various aspects of the wound healing process
  • peptides or proteins increase wound breaking strength.
  • the peptides or proteins of the present invention may also be employed so as to reverse the inhibition of wound healing caused by conditions which depress or compromise the immune system.
  • the peptides or proteins of the present invention may be used in the treatment of external burns and to treat and/or prevent skin and burn infections.
  • the peptides or proteins of the present invention may be used in the treatment of external burns and to treat and/or prevent skin and burn infections.
  • the peptides or proteins of the present invention may be used in the treatment of external burns and to treat and/or prevent skin and burn infections.
  • peptides or proteins may be used to treat skin and burn infections caused by organisms such as, but not limited to, P. aeruqinosa and S aureus
  • the peptides or proteins are also useful in the
  • Such infections may be caused by bacteria such as, but not limited to, P.
  • fungi such as but not limited to C. albicans and A fumigatus
  • parasites such as but not limited to A. castellani, or by viruses.
  • the peptides or proteins may also be effective in killing cysts, spores, or trophozoites of infection-causing organisms.
  • Such organisms include, but are not limited to Acanthamoeba which forms trophozoites or cysts, C.
  • albicans which forms spores
  • A. fumigatus which forms spores as well.
  • antiparasitic amount to prevent or treat microbial or viral or parasitic contamination thereof.
  • the peptides or proteins may also be employed in
  • peptides neutralize bacterial endotoxins.
  • the peptides or proteins are positively charged, while in general, the bacterial endotoxins are negatively charged.
  • the peptides or proteins are particularly useful in that such compounds neutralize bacterial endotoxins without neutralizing essential proteins in plasma (such as heparin, for example).
  • compositions are generally present in an amount of at least 0.1%, by weight. In most cases, it is not necessary to employ the peptide in an amount greater than 2.0%, by weight.
  • the active peptide or protein is present in an amount to achieve a serum level of the peptide of at least about 5 ug/ml.
  • the serum level of peptide or protein need not exceed 500 ug/ ml.
  • a preferred serum level is about 100 ug/ml.
  • Such serum levels may be achieved by incorporating the peptide or protein in a composition to be administered systemically at a dose of from 1 to about 10 mg/kg.
  • the peptide (s) or protein (s) need not be administered at a dose exceeding 100 mg/kg.
  • the peptides or proteins may be produced by known techniques and obtained in substantially pure form.
  • the peptides may be synthesized on an automatic peptide synthesizer. Journal of the American Chemical
  • the N-terminal (NH 2 or amino terminal) of the peptide is reacted such that the lipophilic moiety is attached to the N-terminal of the peptide.
  • the reaction may be a condensation reaction with an amine .
  • the N-terminal is reacted with a carboxylic acid of the formula R-COOH, wherein R is a hydrocarbon having at least 2 carbon atoms.
  • the reaction may be carried out in the presence of a coupling agent, such as, for example, DCC, or DIC, and HOBT, or in the presence of an acid chloride.
  • a coupling agent such as, for example, DCC, or DIC, and HOBT
  • x is a peptide which is a basic
  • hydrophobic amino acids are in groups of two adjacent amino acids, and each group of two hydrophobic amino acids is spaced from another group of two hydrophobic amino acids by at least one amino acid other than a hydrophobic amino acid (preferably at least two amino acids) and generally by no greater than four amino acids, and the amino acids between pairs of hydrophobic amino acids may or may not be hydrophilic.
  • the hydrophilic amino acids are generally also in groups of two adjacent amino acids in which at least one of the two amino acids is a basic hydrophilic amino acid, with such groups of two hydrophilic amino acids being spaced from each other by at least one amino acid other than a hydrophilic amino acid (preferably at least two amino acids) and
  • amino acids generally no greater than four amino acids, and the amino acids between pairs of hydrophilic amino acids may or may not be hydrophobic.
  • the polypeptide comprises a chain of at least four groups of amino acids, with each group consisting of four amino acids. Two of the four amino acids in each group are hydrophobic amino acids, and two of the four amino acids in each group are hydrophilic, with at least one of the hydrophilic amino acids in each group being a basic hydrophilic amino acid and the other being a basic or neutral hydrophilic amino acid.
  • hydrophobic amino acids may be selected from the class consisting of Ala, Cys, Phe, Gly, Ile, Leu, Met, Pro, Val, Trp, Tyr, norleucine (Nle), norvaline (Nva), and
  • the neutral hydrophilic amino acids may be selected from the class consisting of Asn, Gln, Ser, Thr and homoserine (Hse).
  • the basic hydrophilic amino acids may be selected from the class consisting of Lys, Arg, His, Orn, homoarginine (Har), 2, 4-diaminobutyric acid (Dbu), and p-aminophenylalanine.
  • Each of the groups of four amino acids may be of the sequence ABCD, BCDA, CDAB, or DABC, wherein A and B are each hydrophobic amino acids and may be the same or different, one of C or D is a basic hydrophilic amino acid, and the other of C or D is a basic or neutral hydrophilic amino acid and may be the same or different.
  • the polypeptide chain may comprise 5 or 6 groups of this sequence. In each group, each of A, B, C and D may be the same in some or all of the groups or may be different in some or all of the groups.
  • the polypeptide chain preferably has it least 20 amino acids, and no greater than 50 amino acids. It is to be understood, however, that the polypeptide does not have to consist entirely of the groups described above.
  • polypeptide may have amino acids extending from either or both ends of the noted groups forming the polypeptide chain and/or there may be amino acids between one or more of the at least four groups and still remain within the scope of the invention.
  • the groups of amino acids may be repeating groups of amino acids, or the amino acids in the various groups may vary provided that in each group of the at least four groups of amino acids there are two hydrophobic and two hydrophilic amino acids as hereinabove noted.
  • the biologically active polypeptide may comprise a chain including at least four groups of amino acids, each containing four amino acids. Two of the four amino acids in each group are hydrophobic, at least one amino acid is basic hydrophilic, and the remaining one is basic or neutral hydrophilic, with the polypeptide chain preferably having at least 20 amino acids but no greater than 50 amino acids.
  • each of the at least four groups of amin ⁇ -aci.ds which are in the peptide chain is of the sequence A-B-C-D, B-C-D-A, C-D-A-B or D-A-B-C wherein A and B are hydrophobic amino acids, one of C or D is a basic hydrophilic amino acid, and the other of C or D is basic or neutral hydrophilic amino acid.
  • the resulting polypeptide chain therefore, may have one of the following sequences: (X 1 ) a -(A-B-C-D) n (Y 1)b
  • X is D; C-D- or B-C-D-, Y 1 is -A or -A-B or
  • X 2 is A-, D-A- or C-D-A-Y 2 is -B, -B-C or B-C-D
  • X 3 is B-, A-B-, D-A-B-Y 3 is -C, -C-D, -C-D-A
  • X 4 is C-, B-C-, A-B-C-Y 4 is -D, -D-A, -D-A-B
  • n is at least 4.
  • amphiphilicity and a positive charge and do not adversely affect the folding characteristics of the chain to that which is significantly different from one in which the hereinabove noted groups of four amino acids are not spaced from each other.
  • the peptide may have amino acids extending from either end of the chain.
  • the chains may have a Ser-Lys sequence before the "Ala” end, and/or an Ala-Phe sequence after the "Lys" end.
  • Other amino acid sequences may also be attached to the "Ala” and/or the "Lys" end.
  • the chain may have, for example, a C-D sequence before the first A-B-C-D group.
  • other amino acid sequences may be attached to the "A" and/or the "D" end of one of these polypeptide chains.
  • amino acids in the chain which space one or more groups of the hereinabove noted four amino acids from each other.
  • X is a magainin peptide.
  • a magainin peptide is either a magainin such as magainin I, II or III or an analogue or derivative thereof.
  • the magainin peptides preferably include the following basic peptide structure X 12
  • R 14 and R 14a are hydrophobic or basic hydrophilic amino acids
  • R 15 is glutamic acid or aspartic acid, or a hydrophobic or a basic hydrophilic amino acid
  • n is 0 or 1.
  • R 13 is a hydrophobic or neutral hydrophilic amino acid
  • R 14a is a hydrophobic amino acid
  • R 15 is glutamic acid or aspartic acid.
  • -Thus for example, a magainin peptide may include the following structure:
  • a magainin peptide may also have the following
  • R 16 where R 16 is a basic hydrophilic amino acid or asparagine or glutamine.
  • R 16 -R 17 where R 17 is a neutral 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
  • X 12 , Y 12 and Z 12 are as Previously defined and a is 0 or 1 and b is 0 or 1.
  • the magainin peptides may also include the following basic peptide structure X 13 :
  • R 14a are amino acids as hereinabove described.
  • the magainin peptide may also include the following structure X 13 -Z 13 ; wherein X 13 is the hereinabove described basic peptide structure and Z 13 is
  • the magainin peptides generally include at least
  • a magainin peptide preferably has 22 or 23 amino acids.
  • 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-sequences as given in the accompanying sequence listing as well as appropriate analogues and derivatives thereof:
  • Magainin peptides are described in Proc. Natl. Acad. Sci. Vol. 84 pp. 5449-53 (Aug. 87) .
  • magainin peptides refers to the basic magainin
  • X may be a PGLa peptide or an XPF peptide.
  • a PGLa peptide is either PGLa or an analogue or
  • the PGLa peptides preferably include the following basic peptide structure X 14 :
  • R 11 -R 11 -R 12 - where R 11 , R 12 , R 14 , and R 17 are as Previously defined.
  • the PGLa peptides generally include at least seventeen amino acids and may include as many as forty amino acids.
  • structure 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 structure:
  • R 11 and R 14 are as previously defined.
  • a PGLa peptide may also have the following structure :
  • R 11 is as previously defined.
  • a PGLa peptide may also have the following structure:
  • 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
  • the XPF peptides preferably include the following basic 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 asparagine or a basic hydrophilic, or hydrophobic amino acid and, n is 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 for 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 following structure:
  • An XPF peptide may also have the following structure: where X 16, Y16 and Z16 are as previously defined: a is 0 or 1 and b is 0 or 1.
  • X is a CPF peptide or appropriate analogue or derivative thereof.
  • CPF peptides as well an analogues and derivatives thereof are herein sometimes referred to collectively as CPF peptides.
  • the CPF peptide may be one which includes the following basic peptide structure X 20 :
  • R 21 is a hydrophobic acid
  • R 22 is a hydrophobic amino acid or a basic hydrophilic amino acid
  • R 23 is a basic hydrophilic amino acid
  • R 24 is a hydrophobic or neutral hydrophilic amino acid
  • R 25 is a basic or neutral hydrophilic amino acid.
  • hydrophobic amino acids are Ala, Cys, Phe, Gly, lle, Leu, Met, Val, Trp, Tyr, norleucine (Nle), norvaline (Nva), and cyclohexylalanine (Cha).
  • the neutral hydrophilic amino acids are Asn, Gln, Ser, Thr, and homoserine (Hse).
  • the basic hydrophilic amino acids are Lys, Arg, His, Orn, homoarginine (Har), 2,4-diaminobutyric acid (Dbu), and p-aminophenylalanine.
  • the CPF peptide may include only the hereinabove noted amino acids or may include additional amino acids at the amino and/or carboxyl end or both the amino and carboxyl end. In general, the peptide does not include more than 40 amino acids.
  • the CPF peptides including the above basic structure preferably have from 1 to 4 additional amino acids at the amino end.
  • R 2 1 , R 22 and R 25 are as previously defined.
  • the carboxyl end of the basic peptide structure may also have additional amino acids which may range from 1 to 13 additional amino acids.
  • the basic structure may have 1 to 7 additional amino acids at the carboxyl end, which may be represented as follows:
  • X is the hereinabove defined basic peptide structure
  • Preferred peptides may be represented by the following structural formula
  • X 20 , Y 20 and Z are as previously defined and a is 0 or 1 and b is 0 or 1.
  • X is a peptide which includes one of the following basic structures X 31 through X 37 wherein:
  • X 31 is -[R 31 -R 32 -R 32 -R 33 -R 31 -R 32 -R 32 ]- n ;
  • X 32 is -[R 32 -R 32 -R 33 -R 31 -R 32 -R 32 -R 31 ]- n ;
  • X 33 is -[R 32 -R 33 -R 31 -R 32 -R 32 -R 31 -R 32 ]- n ;
  • X 34 is -[R 33 -R 31 -R 32 -R 32 -R 31 -R 32 -R 32 ]- n ;
  • X 35 is - [R 31 -R 32 -R 32 -R 31 -R 32 -R 32 -R 33 ]- n ;
  • X 36 is -[R 32 -R 32 -R 31 -R 32 -R 32 -R 33 -R 31 ]- n ;
  • X 37 is -[R 32 -R 31 -R 32 -R 32 -R 33 -R 31 -R 32 ]- n ;
  • R 31 is a basic hydrophilic amino acid
  • R 32 is a hydrophobic amino acid
  • R 33 is a neutral hydrophilic, basic hydrophilic, or hydrophobic amino acid
  • n is from 1 to 5.
  • the basic hydrophilic amino acids may be selected from the class consisting of Lys, Arg, His, Orn, homoarginine (Har), 2,4-diaminobutyric acid (Dbu), and p-aminophenylalanine.
  • the hydrophobic amino acids may be selected from the class consisting of Ala, Cys, Phe, Gly, lie, Leu, Met, Pro, Val, Trp and Try, norleucine (Nle), norvaline (Nva), and cyclohexylalanine (Cha).
  • the neutral hydrophilic amino acids may be selected from the class consisting of Asn, Gln, Ser, Thr, and homoserine (Hse).
  • the peptide when the peptide includes the structure X 31 , the peptide may include the following structure:
  • Y 31 -X 31 wherein X 31 is as hereinabove described, and Y31 is:
  • the peptide when the peptide includes the structure X 31 , the peptide may include the following structure:
  • the peptide may include the following structure:
  • the peptide may include the following structure:
  • the peptide when the peptide includes the structure X 32 , the peptide may include the following
  • the peptide may include the following structure:
  • the peptide when the peptide includes the structure X 33 , the peptide may include the following structure:
  • X 33 is as hereinabove described, and Y 33 is:
  • the peptide when the peptide includes the structure X 33 , the peptide may include the following structure:
  • the peptide may include the following structure:
  • the peptide when the peptides includes the structure X 34, the peptide may include the following structure:
  • Y 34 is:
  • the peptide when the peptide includes the structure X 34 , the peptide may include the following structure:
  • the peptide may include the following structure:
  • the peptide when the peptide includes the structure X 35 , the peptide may include the following structure:
  • Y 35 is:
  • the peptide when the peptide includes the structure X 35 , the peptide may include the following structure:
  • the peptide may include the following structure:
  • a is 0 or 1
  • b is 0 or 1.
  • the peptide when the peptide includes the structure X 36 , the peptide may include the following structure:
  • the peptide when the peptide includes the structure X 36 .
  • the peptide may include the following structure:
  • the peptide may include the following structure:
  • a is 0 or 1
  • b is 0 or 1.
  • the peptide when the peptide includes the structure X 37 , the peptide may includes the structure Y 37 -X 37 , wherein X 37 is as hereinabove described, and Y 37 is:
  • the peptide when the peptide includes the structure X 37 , the peptide may include the following structure:
  • the peptide may include the following structure:
  • a is 0 or 1
  • b is 0 or 1.
  • n 3
  • peptide is of one of the following structures as given in the accompanying sequence listing:
  • X is a peptide which includes the following basic structure X 40 :
  • the peptide may include the following structure:
  • Y 40 -X 40 , wnerein X 40 is as hereinabove described, and
  • Y 40 is:
  • X is a peptide which includes the following structure:
  • Y 40 ) a -X 40 -(Z 40 ) b wherein Y 40 and Z 40 are as Previously defined, a is 0 or 1, and b is 0 or 1.
  • the peptide has the following structural formula as given in the accompanying sequence listing:
  • the peptide has the following structural formula as given in the accompanying sequence listing:
  • the peptide has one of the one of the following structural formulae as given in the accompanying sequence listing:
  • X is a peptide which includes one of the following structural formulae:
  • n is from 1 to 5.
  • n is 3, and the peptide has one of the following structural formulae:
  • the X is a peptide which is selected from the group consisting of the following structural formulae as given in the accompanying sequence listing:
  • X is a cecropin or sarcotoxin.
  • cecropins includes the basic structure as well as analogues and derivatives thereof.
  • cecropins and analogues and derivatives thereof are described in Ann. Rev. Microbiol. 1987, Vol. 41, pages 103-26, in particular page 108, and in Christensen, et al., PNAS Vol. 85, pgs. 5072-76, which are hereby incorporated by reference.
  • sarcotoxins includes the basic materials as well as analogues and derivatives thereof. The sarcotoxins and analogues and derivatives thereof are described in
  • X is melittin or an analogue or derivative thereof.
  • Melittin is an amphipathic peptide consisting of 26 amino acid residues, and is isolated from honeybee (Apis mellifera) venom. Habermann, et al., Hoppe-Seyler's
  • X is a amphiphilic peptide which includes the following basic structure X 50 :
  • R 41 is a hydrophobic amino acid
  • R 42 is a basic hydrophilic or neutral hydrophilic amino acid.
  • the peptide includes the basic structure Y 50 -X 50 wherein X 50 is as hereinabove described and
  • R 41 is leucine. In another embodiment, R 41 is leucine. In another
  • R 42 is lysine.
  • Representative examples of peptides in accordance with this aspect of the present invention include those having the following structures: (SEQ ID NO: 94)
  • X is an
  • amphiphilic peptide which includes the following basic structure X 52 :
  • R 41 is leucine. In another embodiment, R 41 is leucine. In another
  • R 42 is lysine
  • the peptide includes the basic structure Y 52 -X 52 , where X 52 is as hereinabove described, and
  • Y 52 is:
  • the peptide may have the following structure
  • the peptide includes the basic structure X 52 -Z 52 , where X 52 is as hereinabove described, and
  • the peptide may have the following structure : Lys Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu Leu Lys Lys Leu
  • the peptide may include the structure:
  • X is a biologically active amphiphilic peptide which includes the following basic structure X 54 :
  • R 41 -R 42 -R 42 -R 41 -R 41 -R 42 -R 42 -R 41 -R 42 -R 42 -R 41 -R 41 -R 42 -R 42 -R 43 wherein R 41 and R 42 are as hereinabove described, and R 43 is a neutral hydrophilic amino acid.
  • the peptide may have the following structure:
  • the peptide may have the following amino acids:
  • X is a biologically active amphiphilic peptide which includes the following basic structure X 56 :
  • R 42 are as hereinabove described, and R 44 is a neutral hydrophilic amino acid or proline.
  • the peptide may include the
  • the peptide may have one of the following structures:
  • X is a biologically active amphiphilic peptide which includes the following basic structure X 58 :
  • R 41 , R 42 , and R 43 are as hereinabove described.
  • the peptide includes the structure
  • X 58 -Z 58 wherein X 58 is as hereinabove described, and Z 58 is (i) -R 41 ;
  • the peptide has the following structure:
  • X is a biologically active amphiphilic peptide which includes the following basic structure X 60 :
  • the peptide may have the following structure:
  • X is a peptide which includes the following basic structure X 62 :
  • the peptide includes the following structure Y 62 - X 62 , where X 62 is as hereinabove described, and Y 62 is:
  • the peptide includes the structure X 62 -Z 62 , wherein X 62 is as hereinabove described, and Z 62 is (i) R 41
  • the peptide has the structure
  • X is a peptide having the
  • X is a biologically active amphiphilic peptide including the following basic structure X 64 :
  • R 41 and R 42 are as hereinabove described.
  • the peptide may include the structure
  • Y 64 -X 64 - wherein X 64 is as hereinabove described, and Y 64 is :
  • the peptide may include the structure X 64 -Z 64 , wherein X 64 is as hereinabove described, and Z 64. is:
  • the peptide has the amino acid sequence: (a)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl
  • X is a biologically active amphiphilic peptide including the following basic structure
  • a representative example of such a peptide is the following:
  • X is a biologically active amphiphilic peptide including the following basic structure
  • R 41 , R 42 , and R 46 are hereinabove described.
  • the peptide includes the following basic structure Y 68 -X 68 , wherein X 68 is as hereinabove described, and Y 68 is:
  • X is a biologically active amphiphilic peptide including the following basic structure X 70 :
  • X is a biologically active amphiphilic peptide including the following basic structure X 72 :
  • R 41 and R 42 are hereinabove described, and R 47 is aspartic acid.
  • a representative example of such a peptide has the following structure:
  • X is a biologically active amphiphilic peptide having the following structure:
  • X is a biologically active amphiphilic peptide including the following structure X 74 : R 42 -R 41 -R 42 -R 41 -R 41 -R 42 -R 42 -R 41 -R 46 -R 42 -R 41 , wherein R 41 , R 40 , and R 46 are hereinabove described.
  • X is a biologically active amphiphilic peptide including the following structure X 76 :
  • R 41 and R 42 are hereinabove described.
  • the peptide includes the
  • the peptide includes the
  • R 48 is a basic hydrophilic, neutral hydrophilic, or hydrophobic amino acid.
  • the peptide has the following structural formula:
  • X is a biologically active amphiphilic peptide including the following structural formula X 78 :
  • X has the following structure:
  • X is a biologically active amphiphilic peptide including the following structural formula X 80 :
  • R 41 , R 42 , and R 46 are as hereinabove described.
  • X is an ion channel-forming peptide or protein.
  • Ion channel-forming proteins or peptides which may be employed include defensins, also known as human neutrophil antimicrobial peptides (HNP), major basic protein (MBP) of eosinophils, bactericidal permeability-increasing protein (BPI), and a pore-forming cytotoxin called variously
  • defensins also known as human neutrophil antimicrobial peptides (HNP), major basic protein (MBP) of eosinophils, bactericidal permeability-increasing protein (BPI), and a pore-forming cytotoxin called variously
  • perforin perforin, cytolysin, or pore-forming protein.
  • Defensins are described in Selsted, et al., J. Clin. Invest., Vol. 76, pgs. 1436-1439 (1985).
  • MBP proteins are described in
  • ion channel-forming proteins includes the basic structures of the ion channel -forming proteins as well as analogues and derivatives.
  • each of the amino acid residues of the peptides or proteins may be a D-amino acid or glycine.
  • the scope of this particular embodiment is not to be limited to any theoretical reasoning, it is believed that the above-mentioned peptides or proteins, when consisting entirely of D-amino acid or glycine residues, may have increased resistance to proteolytic enzymes while retaining their activity. Such peptides thus may be
  • all of the amino acid residues may be D-amino acid or glycine residues, or L-amino acid or glycine
  • proteins may be administered in combination with one another.
  • N-terminal substituted peptides or proteins of the present invention may be employed in combination with an ion having phamacological properties for the purposes hereinabove described.
  • An ion having pharmacological properties is one which when introduced into a target cell or virus or
  • virally-infected cell inhibits and/or prevent and/or destroys the growth of the target cell, virus or virally-infected cell.
  • Such an ion having pharmacological properties is one which in the absence of an ion channel forming peptide is unable to cross a natural or synthetic lipid membrane; in particular a cell or virus membrane, in sufficient amounts to affect a cell or virus adversely.
  • the peptide or protein and ion having pharmacological properties may be administered as a single composition or in separate compositions, and the single or separate
  • compositions may include additional materials, actives and/or inactives, in addition to the peptide or protein and ion having pharmacological properties.
  • additional materials actives and/or inactives, in addition to the peptide or protein and ion having pharmacological properties.
  • ions having pharmacological properties which may be employed, there may be mentioned fluoride, peroxide, bicarbonate, silver, zinc, mercury, arsenic, copper, platinum, antimony, gold, thallium, nickel, selenium,
  • pharmacological properties whether administered or prepared in a single composition or in separate compositions, are employed in amounts effective to inhibit and/or prevent and/or destroy the growth of the target cell, virus, or virally-infected cell.
  • the ion potentiates the action of the peptide, i.e., the amount of ion is effective to reduce the maximum effective concentration of the peptide or protein for inhibiting growth of a target cell, virus, or virally-infected cell.
  • the ion having pharmacological properties when used topically, is generally employed in a concentration of from 0.05% to 2.0%. When used systemically, the ion is generally employed in an amount of from 1 to 10 mg. per kg. of host weight. Peptide or protein dosages may be within the ranges hereinabove described.
  • the peptide or protein and ion having pharmacological properties may be delivered or administered in different forms; for example, the ion may be administered orally, while the peptide may be administered by IV or IP.
  • the peptide could be administered in an amount of up to about 1% weight to weight and the ion delivered in an amount of about 50mM (about 0.1%).
  • the ion in the form of a salt such as sodium fluoride, could be administered orally in conjunction with systemic administration of the peptide or protein.
  • the peptide or protein may be
  • the peptides or proteins of the present invention may be administered to a host in combination with an antibiotic selected from the class consisting of bacitracins, gramacidin, polymyxin, vancomycin, teichoplanin, aminoglycosides, hydrophobic antibiotics, penicillins, monobactams, or derivatives or analogues thereof.
  • an antibiotic selected from the class consisting of bacitracins, gramacidin, polymyxin, vancomycin, teichoplanin, aminoglycosides, hydrophobic antibiotics, penicillins, monobactams, or derivatives or analogues thereof.
  • the bacitracins are a group of polypeptide antibiotics.
  • a preferred bacitracin is bacitracin A.
  • Aminoglycoside antibiotics include tobramycin,
  • kanamycin amikacin
  • the gentamicins e.g., gentamicin C 1 . gentamicin C 2 , gentamicin C 1a
  • netilmicin netilmicin
  • derivatives and analogues thereof The preferred aminoglycosides are tobramycin and the gentamicins.
  • the aminoglycosides, and the bacitracins hereinabove described, tend to be hydrophilic and water-soluble.
  • Penicillins which may be employed include, but are not limited to benzyl penicillin, ampicillin, methicillin
  • Preferred penicillins which may be employed are benzyl penicillin and ampicillin.
  • a preferred monobactam which may be employed is aztreonam.
  • hydrophobic antibiotics which may be used in the present invention, there may be mentioned macrolides such as erythromycin, roxythromycin, clarithromycin, etc.; 9-N-alkyl derivatives of erythromycin; midecamycin acetate; azithromycin; flurithromycin; rifabutin; rokitamycin; a 6-0-methyl erythromycin A known as TE-031 (Taisho); rifapentine; benzypiperazinyl rifamycins such as CGP-7040, CGP-5909, CGP-279353 (Ciba-Geigy); an
  • difficidin a 3-N-piperdinomethylzaino methyl rifamycin SV known as FCE-22250 (Farmitalia); M-119-a (Kirm Brewery); a 6-O-methyl-1-4"-O-carbamoyl erythromycin known as A-63075 (Abbott); 3-formylrifamycin SV-hydrazones with diazabicycloalkyl side chains such as CGP-27557 and CGP-2986 (Ciba-Geigy); and 16-membered macrolides having a
  • rifamycin carbenicillin, and nafcillin may be employed as well.
  • antibiotics which may be used are antibiotics which are 50-S ribosome
  • inhibitors such as lincomycin; clindamycin; and
  • chloramphenicol; etc. antibiotics which have a large lipid like lactone ring, such as mystatin; pimaricin, etc.
  • the peptide or protein and antibiotic may be
  • Target cells whose growth may be prevented, inhibited, or destroyed by the administration of the peptides and antibiotic include Gram-positive and
  • Gram-negative bacteria as well as fungal cells.
  • the antibiotic such as those hereinabove described, or derivatives or analogues thereof, when used topically, is generally employed in a concentration of about 0.1% to about 10%.
  • the antibiotic or derivative or analogue thereof when used systemically, is generally employed in an amount of from 1.25 mg. to about 45 mg. per kg. of host weight per day.
  • Peptide or protein dosages may be those as hereinabove described.
  • the peptide or protein could be administered in an amount of from about 0.1% to about 10% weight to weight, and the antibiotic is delivered in an amount of from about 0.1% to about 10% weight to weight.
  • the peptides or proteins of the present invention may be administered in combination with an antiparasitic agent or an antifungal agent.
  • Antiparasitic agents which may be employed include, but are not limited to, anti-prot-zoan agents.
  • Examples of specific anti-parasitic agents which may be employed include, but are not limited to, pentamidine isethionate, and
  • Anti-fungal agents which may be employed include, but are not limited to, ketoconazole. It is also to be
  • anti-parasitic agents may also have anti-fungal activity, and that certain anti-fungal agents may have anti-parasitic activity.
  • the peptides or proteins of the present invention may be administered in combination with an antibiotic which inhibits DNA gyrase, which is an enzyme involved in the formation of bonds between individual coiling strands of replicating bacterial DNA.
  • DNA gyrase is necessary for the normal replication of bacterial DNA, and, therefore, antibiotics which inhibit DNA gyrase inhibit the normal replication of bacterial DNA.
  • antibiotics which inhibit DNA gyrase include nalidixic acid, oxolinic acid, cinoxacin, and quinolone antibiotics which include ciprofloxacin, norfloxacin, ofloxacin, enoxacin, pefloxacin, lomefloxacin, fleroxacin, tosulfloxacin, temafloxacin, and rufloxacin.
  • Table I which follows, indicates the Minimal Inhibitory Concentration (MIC) in ⁇ g/ml of various peptides, against
  • a "D” indicates that each amino acid residue is a D-amino acid residue or a glycine residue.
  • the peptides are unsubstituted at the N-terminal, substituted with an acetyl group at the N-terminal as indicated by Ac-; substituted with an octanoyl group at the N-terminal as indicated by Oct-, substituted with sphingosine as indicated by Sph-;
  • Each peptide is a C-terminal amide.
  • the stock peptide solution is diluted in serial
  • viscosus are maintained on Brucella blood agar plates with hemin and vitamin K (BBL, Cockeysville, MD) and are grown under anaerobic conditions (Coy Anaerobic Chamber, Ann Arbor, MI) with an atmosphere of 80% N 2 -10%H 2 -1-%CO 2 at 37°C.
  • CFUs colony-forming units
  • NCCLS National Committee for Clinical Laboratory Standards
  • Microtiter plates (Corning, Corning, NY) are filled aseptically with BHI broth (plus hemin plus vitamin K 1 ) to a volume of 100 ⁇ l by the use of a Beckman Biomek 1000 robotic instrument (Beckman Instruments, Palo Alto, CA). Peptides are tested in duplicate lanes by adding manually 100 ⁇ l of a 1.024 mg/ml peptide solution in water (w/v) to the top wells of a microtiter plate lane. The peptide is diluted serially 1:2 by mixing and transferring 100 ⁇ l from the top well down to the bottom well in the lane by use of the Beckman Biomek 1000 (Beckman Instruments, Palo Alto, CA).
  • MIC minimum inhibitory concentration
  • mice were injected intravenously via the tail vein at 1 and 5 hours post-inoculation. Control mice were
  • Oct-(SEQ ID NO:143)-NH was injected intravenously into male C57BL/6J mice (average body weight, 20.1g) approximately two minutes prior to intraperitoneal injection of a solution of lipopolysaccharide (either 0.1 ⁇ g or 0.5 ⁇ g mouse) from E. coli serotype 0111 :B4 and galactosamine (8 mg/mouse*.
  • Treatment doses of Oct.-(SEQ ID NO:143)-NH were 0, 5, 7.5, 10, 12.5, or 15 mg/kg (10 mice/group), and when administered prior to 0.5 ⁇ g lipopolysaccharide/mouse resulted in 10%, 0%, 30%, 0%, 50%, and 60% survival at five days
  • a stock solution (10x) of 0.6 mM dye is prepared by adding 1.68 mg of (1-ethyl-2-(3-[1-ethylnapthol(1,2-d)-thiazolin-2- ylidene]-2-methylpropenyl)naphtho-(1,2-d)-thiazolium bromide (Signa E-7762) to 5 ml of 200 proof ethanol. 1 ml of this solution was added to 9 ml ethanol to give 0.06 mM of dye (60 ⁇ M dye).
  • LPS lipopolysaccharide
  • Row 1 and rows 3 through 12 of a microtiter plate were filled with 100 ⁇ l of pyrogen free water or with 10 mg/ml of bovine serum albumin. 200 ⁇ l of peptide then is added to row 2 of the microtiter plate at a concentraiton of 1 ml/ml. 200 ⁇ l of pyrogen free water is added to each of the control wells in two lanes (having dye and LPS but no peptide or having dye and no LPS and no peptide). 100 ⁇ l then is serially diluted from row 2 through row 12 of the microtiter plate. 50 ⁇ l of PBS (pH 7.4) and 50 ⁇ l of the LPS solution then are added to row 1 of the plate (blank wells) .
  • PBS pH 7.4
  • 50 ⁇ l of the LPS solution then are added to row 1 of the plate (blank wells) .
  • Equal volumes of the LPS solution, the dye, and PBS (pH 7.4, approx. 150 mM) are mixed to form a dye-buffer - LPS mixture having LPS at a final concentration of 20 ⁇ M.
  • the dye-buffer LPS mixture then is incubated for 10 minutes at room temperature in the dark.
  • 100 6 ⁇ l of the dye-LPS-buffer mixture then is added to every well of the microtiter plate except to the blank wells and to the control lane that does not have LPS or peptide.
  • the plate is incubated for 10 minutes at room temperature in the dark and the absorbance at 460 nm and 510 nm is read.
  • concentration in ⁇ g/ml of peptide necessary to inhibit the binding of 50% of the lipopolysaccharide to the dye is calculated.
  • peptides or proteins of the present invention may be employed in a wide variety of pharmaceutical compositions in combination with a non-toxic pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or physiological saline solution.
  • a non-toxic pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or physiological saline solution.
  • compositions may be used topically or
  • peptides or proteins and/or agent as hereinabove described may also be used in combination with adjuvants, protease inhibitors, or compatible drugs where such a combination is seen to be desirable or advantageous in controlling infection caused by harmful microorganisms including protozoa, viruses,
  • the peptides or proteins may be administered to a host in particular an animal, in an effective antibiotic and/or anti-tumor and/or antiviral and/or antimicrobial and/or antispermicidal and/or antifungal and/or antiparasitic amount, or in an amount effective to stimulate wound healing in a host, or in an amount effective in treating septic shock in a host.
  • the peptides or proteins may be administered either alone or in combination with an ion having
  • peptide or protein is administered in combination with an ion having pharmacological properties, the activity of the peptide or protein is potentiated.
  • the agent may be administered
  • peptide or protein may be administered topically.
  • the peptide or protein When the peptide or protein is administered topically, it may be administered in combination with a water-soluble vehicle, said water-soluble vehicle being in the form of an ointment, cream, lotion paste or the like.
  • a water-soluble vehicle which may be employed include, but are not limited to, glycols, such as polyethylene glycol,
  • the water-soluble vehicle is preferably free of an oil substance.
  • the peptide or protein may also be employed alone, or in combination with an ion having pharmacological properties, as hereinabove described in the form of an oral composition for oral hygiene.
  • Such a composition may be incorporated into a wide variety of compositions and materials used for oral hygiene purposes, which include, but are not limited to, toothpastes, mouthwashes, tooth gels, and tooth powders.
  • composition may thus be used to treat or prevent
  • the peptide and ion having pharmacological properties may be used to inhibit, prevent, or destroy the growth of Streptococcus mutans. which is associated with dental caries and
  • ADDRESSEE Carella, Byrne, Bain,

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Abstract

Peptide ou protéine à substitution N-terminale correspondant à la formule (1), dans laquelle X est un peptide ou protéine biologiquement actif formant un canal ionique amphiphilique, T est une fraction lipophile et, de préférence, représente (2) (où R est un hydrocarbure (alkyle ou aromatique ou alkylaromatique) comportant au moins 2 et au maximum 10 atomes de carbone. T est de préférence un groupe octanoyle. W est T ou hydrogène. Ces peptides et protéines à substitution N-terminale présentent une activité biologique améliorée contre des cellules cibles, des virus et des cellules infectées par un virus.
PCT/US1995/000714 1994-01-18 1995-01-18 Peptides amphiphiliques formant des canaux ioniques et presentant des modifications n-terminales WO1995019370A1 (fr)

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EP95909267A EP0750632A1 (fr) 1994-01-18 1995-01-18 Peptides amphiphiliques formant des canaux ioniques et presentant des modifications n-terminales
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Cited By (7)

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WO1999003488A3 (fr) * 1997-07-15 1999-04-08 Magainin Pharma Peptides biologiquement actifs a toxicite reduite chez l'animal et procedes d'elaboration
NL1008745C2 (nl) * 1998-03-30 1999-10-01 Stichting Tech Wetenschapp Therapeutisch werkzame verbinding voor behandeling van gist- en/of schimmelinfecties in de mondholte.
WO2002028438A1 (fr) * 2000-10-05 2002-04-11 King's College London Lipopeptides activateurs d'absorption pour composes bio-actifs
WO2001060162A3 (fr) * 2000-02-15 2002-05-02 Univ Ohio Peptides cationiques presentant une structure secondaire amphipatique de feuillet beta et leurs utilisations
WO2001098362A3 (fr) * 2000-06-16 2002-12-05 Hercules Inc Peptides modifies chimiquement, compositions et leur procede de production et d'utilisation
US6531446B1 (en) * 1998-01-22 2003-03-11 Korea Advanced Institute Of Science And Technology Peptides having biological activity
WO2006086321A2 (fr) * 2005-02-09 2006-08-17 Helix Biomedix Inc. Hexapeptides antimicrobiens

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WO1993005802A1 (fr) * 1991-09-13 1993-04-01 Magainin Pharmaceuticals Inc. Compositions peptidiques amphiphiles biologiquement actives et utilisations desdites compositions
WO1993024138A1 (fr) * 1992-06-01 1993-12-09 Magainin Pharmaceuticals, Inc. Peptides biologiquement actifs presentant des substitutions n-terminales
WO1994013697A1 (fr) * 1992-12-07 1994-06-23 Magainin Pharmaceuticals, Inc. Traitement de chocs septiques au moyen de peptides biologiquement actifs conjugues

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WO1991012015A1 (fr) * 1990-02-08 1991-08-22 Magainin Sciences Inc. Peptides amphiphiles biologiquement actifs et procede pour inhiber la croissance de cellules cibles, de virus ou de cellules contaminees par virus
WO1993005802A1 (fr) * 1991-09-13 1993-04-01 Magainin Pharmaceuticals Inc. Compositions peptidiques amphiphiles biologiquement actives et utilisations desdites compositions
WO1993024138A1 (fr) * 1992-06-01 1993-12-09 Magainin Pharmaceuticals, Inc. Peptides biologiquement actifs presentant des substitutions n-terminales
WO1994013697A1 (fr) * 1992-12-07 1994-06-23 Magainin Pharmaceuticals, Inc. Traitement de chocs septiques au moyen de peptides biologiquement actifs conjugues

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999003488A3 (fr) * 1997-07-15 1999-04-08 Magainin Pharma Peptides biologiquement actifs a toxicite reduite chez l'animal et procedes d'elaboration
US6531446B1 (en) * 1998-01-22 2003-03-11 Korea Advanced Institute Of Science And Technology Peptides having biological activity
NL1008745C2 (nl) * 1998-03-30 1999-10-01 Stichting Tech Wetenschapp Therapeutisch werkzame verbinding voor behandeling van gist- en/of schimmelinfecties in de mondholte.
WO2001060162A3 (fr) * 2000-02-15 2002-05-02 Univ Ohio Peptides cationiques presentant une structure secondaire amphipatique de feuillet beta et leurs utilisations
WO2001098362A3 (fr) * 2000-06-16 2002-12-05 Hercules Inc Peptides modifies chimiquement, compositions et leur procede de production et d'utilisation
US6858581B2 (en) 2000-06-16 2005-02-22 Arizona State University Chemically-modified peptides, compositions, and methods of production and use
WO2002028438A1 (fr) * 2000-10-05 2002-04-11 King's College London Lipopeptides activateurs d'absorption pour composes bio-actifs
WO2006086321A2 (fr) * 2005-02-09 2006-08-17 Helix Biomedix Inc. Hexapeptides antimicrobiens
WO2006086321A3 (fr) * 2005-02-09 2007-02-22 Helix Biomedix Inc Hexapeptides antimicrobiens
US7407940B2 (en) 2005-02-09 2008-08-05 Helix Biomedix Inc. Antimicrobial hexapeptides

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EP0750632A1 (fr) 1997-01-02

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