EP0528861A4 - Composition and treatment with biologically active peptides and toxic cations - Google Patents

Composition and treatment with biologically active peptides and toxic cations

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Publication number
EP0528861A4
EP0528861A4 EP19910908780 EP91908780A EP0528861A4 EP 0528861 A4 EP0528861 A4 EP 0528861A4 EP 19910908780 EP19910908780 EP 19910908780 EP 91908780 A EP91908780 A EP 91908780A EP 0528861 A4 EP0528861 A4 EP 0528861A4
Authority
EP
European Patent Office
Prior art keywords
cations
peptide
silver
cation
amino acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP19910908780
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English (en)
Other versions
EP0528861A1 (fr
Inventor
Barry Berkowitz
Leonard Jacob
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Magainin Pharmaceuticals Inc
Original Assignee
Magainin Sciences Inc
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Filing date
Publication date
Application filed by Magainin Sciences Inc filed Critical Magainin Sciences Inc
Publication of EP0528861A1 publication Critical patent/EP0528861A1/fr
Publication of EP0528861A4 publication Critical patent/EP0528861A4/en
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/242—Gold; Compounds thereof
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A61K38/1751—Bactericidal/permeability-increasing protein [BPI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic 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
    • A61P31/04—Antibacterial agents
    • 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

Definitions

  • This invention relates to biologically active peptides and proteins, and more particularly to compositions and uses involving biologically active peptides or proteins and toxic cations, in particular silver cations.
  • compositions may be employed in preventing and/or treating ocular infections.
  • Silver-containing compositions such as silver nitrate have been used for preventing and/or treating external ocular infections, such as, for example, the prevention and treatment of ophthalmic gonorrhea.
  • Darrell, et al., Tr. Am. Ophth. Soc, Vol. 82 (1984), 75-91 discloses the use of silver norfloxacin, or silver sulfadiazine, or silver sulfacetamide to treat corneal infections caused by P.aeruqinosa. These compounds also exhibit significant biological activity against S.aureus, as well as the fungi C.albicans, and A.fumigatus.
  • composition which includes at least one biologically active amphiphilic peptide and/or biologically active protein; and a toxic cation.
  • a process wherein there is administered to a host at least one biologically active amphiphilic peptide which is an ion channel-forming peptide and/or a biologically active protein which is an ion channel-forming protein and a toxic cation.
  • 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.
  • an ion channel-forming peptide or ion channel forming protein is a peptide or protein which has ion channel-forming properties as determined by the method of Christensen et al.
  • amphiphilic peptide is a peptide which includes both hydrophobic and hydrophilic peptide regions.
  • biologically active peptide or protein and toxic cation 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 and/or protein and toxic cation.
  • compositions of the present invention thus may be used in the treatment of external burns and to treat and/or prevent skin and burn infections.
  • the compositions may be used to treat skin and burn infections caused by organisms such as, but not limited to, P. aeruqinosa and S. aureus.
  • 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.
  • such peptides are non-hemolytic; i.e., they will not rupture blood cells at effective concentrations.
  • the structure of such peptide provides for flexibility of the peptide molecule. When the peptide is placed in water, it does not assume an amphiphilic structure. When the peptide encounters an oily surface or membrane, the peptide chain folds upon itself into a rod-like structure.
  • such peptides have at least 16 amino acids, and preferably at least 20 amino acids. In most cases, such peptides do not have in excess of 40 amino acids.
  • Toxic cations which may be employed include, but are not limited to, silver cations, zinc cations, mercury cations, arsenic cations, copper cations, platinum cations, antimony cations, gold cations, thalluim cations, nickel cations, selenium cations, bismuth cations, and cadmium cations.
  • the toxic cation is a silver cation, which may be employed as part of a suitable compound.
  • suitable silver-containing compounds which may be employed include silver nitrate, silver acetate, silver benzoate,- silver carbonate, silver iodate, silver iodide, silver lactate, silver laurate, silver oxide, silver palmitate, mild silver proteins, and silver sulfadiazine. It is also preferred that the silver-containing composition be water-soluble.
  • the toxic cation may be silver nitrate.
  • Silver nitrate as a 0.5% solution is used in the treatment of external burns, and silver sufladiazine is also used to treat external burns, but bacterial resistance to the sulfonamides (sulfadiazine) can result.
  • S. Harvey in Goodman and Gilman, Pharmacological Basis of Therapeutics, 7th ed. , pgs. 966-967; MacMillan (1985).
  • the peptide or protein is administered topically at a concentration of from .05% to 5%.
  • the toxic cation in general, is used topically at a concentration of from 0.05% to 2.0%.
  • compositions may also be used as antifungal agents to inhibit the growth of or destroy fungi.
  • compositions may also be used as anti-parasitic agents to inhibit the growth of or destroy parasites.
  • compositions have a broad range of potent antibiotic activity against a plurality of microorganisms, including gram-positive and gram-negative bacteria, fungi, protozoa parasites, and the like. Such compositions may be employed for treating or controlling microbial infection caused by organisms which are sensitive to such compositions.
  • the treatment may comprise administering to a host organism or tissues acceptable to or affiliated with a microbial infection an anti-microbial amount of peptide or protein and toxic cation.
  • compositions may also be effective in killing cysts, spores, or trophozoites of infection-causing organisms.
  • organisms include, but are not limited to Acanthamoeba which forms trophozoites or cysts, C. albicans, which forms spores, and A. fumigatus, which forms spores as well.
  • the peptide used in conjunction with a toxic cation is a basic (positively charged) polypeptide having at least sixteen amino acids wherein the polypeptide includes at least eight hydrophobic amino acids and at least eight hydrophilic amino acids.
  • the 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 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.
  • 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 at 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.
  • the 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 comprises 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 amino acids 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 basic hydrophilic amino acid, and the other of C or D is basic or neutral hydrophilic amino acid.
  • the resulting polypeptide chain may have one of the following sequences: (X 1 ) a (A-B-C-D) n (Y 1 ) b (X 2 )(B-C-D-A) n (Y 2 ) b (X 3 ) a (C-D-A-B) n (Y 3 ) b (X 4 ) a (D-A-B-C) n (Y 4 ) b wherein X-, is D; C-D- or B-C-D-, Y 1 is -A or -A-B or -A-B-C
  • Y 2 is -B, -B-C or B-C-D
  • 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 a is o or 1; b is o or 1 and n is at least 4
  • the peptide chain may include amino acids between the hereinabove noted groups of four amino acids provided that the spacing between such groups and the charge on the amino acids does not change the characteristics of the peptide chain which provide 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 group 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.
  • the peptides may be produced by known techniques and obtained in substantially pure form
  • the peptides may be synthesized on an automatic synthesizer. Journal of American Chemical Society, Vol 85 Pages 2149-54(1963). It is also possible to produce such peptides by genetic engineering techniques.
  • the peptide employed in conjunction with a toxic cation may be 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
  • R.._. is a hydrophobic amino acid
  • R._ is a basic hydrophilic amino acid
  • R. is a hydrophobic, neutral hydrophilic, or basic hydrophilic amino acid
  • R 14 and R- 4 are hydrophobic or basic hydrophilic amino acids
  • R- 5 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 ⁇ 4a is a hydrophobic amino acid
  • R 15 is glutamic acid or aspartic acid.
  • a magainin peptide may include the following structure:
  • a magainin peptide may also have the following structure: "X 12 "Z 12 " wherein X. is as previously defined and Z 19 is:
  • R lg where R lg is a basic hydrophilic amino acid or asparagine or glutamine.
  • R, g -R.- where R_._ is a neutral hydrophilic amino acid, a hydrophobic amino acid, or a basic hydrophilic amino acid.
  • R..- is a neutral hydrophilic amino acid.
  • R. may also have the following structure: where - ⁇ 2 Y 12 anc z i 2 are as Previously defined and a is 0 or 1 and b is 0 or 1.
  • the magainin peptide may also include the following structure Xi 3 ⁇ z 13 ; wherein X 13 is the hereinabove described basic peptide structure and Z 13 is
  • R ll n ⁇ R ll ) n- ⁇ R ll ) n- ⁇ R 14a)n-( R 15 ) n-( R 14a>n ⁇ R 14>n- ⁇ R 16)n- (R 17 ) n
  • R- ⁇ , R 14 , R 14a 15 . lg , and R ⁇ 7 are as hereinabove described, and n is 0 or 1, and each n may be the same or different.
  • magainin peptides having the following primary sequence (expressed as a single letter code) as well as appropriate analogues and derivatives thereof:
  • the peptide employed in conjunction with a toxic cation may be a PGLa peptide or an XPF peptide.
  • a PGLa peptide is either PGLa or an analogue or derivative thereof.
  • the PGLa peptides preferably include the following basic peptide structure 14 :
  • R-,-,, R ⁇ 2 ' R i4' and R 17 are as Previously defined.
  • a PGLa peptide may have the following structure:
  • a PGLa peptide may also have the following • structure:
  • a PGLa peptide may also have the following structure: where X 14 ; Y 14 and Z., 4 are as previously defined, a is 0 or 1 and b is 0 or 1.
  • An XPF peptide is either XPF or an analogue or derivative thereof.
  • the XPF peptides preferably include the following basic peptide structure X l ⁇ :
  • the XPF peptides generally include at least nineteen amino acids and may include up to forty amino acids. Accordingly, the hereinabove described basic peptide structure of XPF may include additional amino acids at the amino end, or at the carboxyl end or at both the amino and carboxyl ends.
  • An XPF peptide may include the following structure:
  • An XPF peptide may also have the following structure:
  • X-, ⁇ Y l ⁇ and Z l ⁇ are as previously defined: a is 0 or 1 and b is 0 or 1.
  • XPF or PGLa peptides which are characterized by the following primary amino acid sequence(single letter amino acid code)
  • the peptide employed in conjunction with a toxic cation may be a CPF peptide or appropriate analogue or derviative thereof.
  • CPF peptides as well as analogues and derivatives thereof are herein sometimes referred to collectively as CPF peptides.
  • the CPF peptide is preferably one which includes the following peptide structure X 3Q :
  • R 23 is a basic hydrophilic amino acid
  • R 24 is a hydrophobic or neutral hydrophilic amino acid
  • hydrophobic amino acids are Ala, Cys, Phe, Gly, lie, Leu, Met, Val, Trp, and Tyr.
  • the neutral hydrophilic amino acids are Asn, Gin, Ser, and Thr.
  • the basic hydrophilic amino acids are Lys, Arg, His and omithine.
  • the CPF peptide may include only the hereinabove noted amino acids or may include additional amino acids at the amino end 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 peptide structure may have from 1 to 4 additional amino acids at the amino end.
  • such preferred peptides may be represented by the structural formula: v -Y - x 30 30 wherein X- 0 is the hereinabove described basic peptide structure and Y 3Q is
  • R 25 - (i) R 25 -, or ( ii) 22 - 25 ' or (iii) R 2 ⁇ - R 22 - R 25 ' or (iv) R 22" R 21" R 22 _R 25 ;
  • R 2 -, R 22 , and R 25 are as previously defined.
  • CPF peptides which are useful in the present invention some of which have been described in the literature and comprise the following sequences (single letter amino acid code):
  • an ion channel-forming protein may be used in conjunction with a toxic cation.
  • Ion channel-forming proteins 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 perforin, cytolysin, or pore-forming protein.
  • HNP human neutrophil antimicrobial peptides
  • MBP major basic protein
  • a pore-forming cytotoxin called variously 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 Wasmoen,
  • Peptide 1 is of the following structure: [KIAGKIAJ 3
  • Peptide 2 is of the following structure: KIAGKIAKIAGOIAKIAGKIA.
  • Peptide 2 was added in increasing concentrations from 0.25 to 256 ⁇ g/ml in the absence of or the presence of silver nitrate.
  • Cecropin A-D was added in increasing amounts from 0.25 ⁇ g/ml to 256 ⁇ g/ml in the absence of or in the presence of silver nitrate. Cecropin A-D is of the following structure:
  • Example 6 Approximately 1-5 x 10 CFUs of P. aeruginosa strain 107 which was gentamicin resistant, dispersed in 100 ⁇ l of TSB were added to each test well. Magainin II (amide-termianted) was added in increasing amounts from 0.25 to 256 ⁇ g/ml in the absence of or in the presence of silver nitrate. The following combinations of Magainin II, with or without silver nitrate, were tested for Minimum Inhibitory Concentration (MIC) of Magainin II:
  • the checkerboard assay was carried out in a 96-well microtiter plate.
  • the plate has twelve rows (Rows 1 through 12), and eight columns (Columns A through H) of wells.
  • 100 ⁇ l of p-lain broth is added to each well of the 96-well plate.
  • lOO ⁇ l of a 4X concentration of Peptide 3 is added to Row 1 and 100 ⁇ l is serially diluted 1:2 from Row 1 to Row 11.
  • Concentrations of Peptide 3 range from 1 to 1,024 ⁇ g/ml.
  • Silver nitrate (AgNO.,) is serially diluted 1:2 at 4X the final desired concentration in a set of tubes. Each 4X solution of silver nitrate is then added to the appropriate column of the microtiter plate.
  • An FIC value of 0.5 or less is indicative of synergy, a value of greater than 0.5 but less than 2 is indicative of indifference, and a value greater than 2 is indicative of antagonism.
  • the following combinations of Peptide 3 and silver nitrate were found to be inhibitory, and the FIC values of each combination are given herewith.
  • the peptide or protein and/or toxic cation 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.
  • Such pharmaceutical compositions may be used topically or systemically and may be in any suitable form such as a liquid, solid, semi-solid, injectable solution, tablet, ointment, lotion, paste, capsule, or the like.
  • the peptide or protein and/or toxic cation 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, parasites and the like.
  • the peptide(s) or protein of the present invention may be administered to a host; in particular an animal, in an effective antibiotic and/or anti-viral and/or anti-microbial and/or anti-parasitic amount in conjunction with a toxic cation for potentiating the activity of the peptide or protein.

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Abstract

Composition comprenant un peptide formant des canaux d'ions amphiphiliques ou une protéine formant des canaux d'ions biologiquement actifs ainsi qu'un cation toxique, tel qu'un cation d'argent. On peut employer lesdites compositions en tant qu'agents pharmaceutiques, notamment dans le traitement et la prévention d'infections oculaires.
EP19910908780 1990-04-23 1991-04-18 Composition and treatment with biologically active peptides and toxic cations Ceased EP0528861A4 (en)

Applications Claiming Priority (2)

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US51234590A 1990-04-23 1990-04-23
US512345 1990-04-23

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EP0528861A1 EP0528861A1 (fr) 1993-03-03
EP0528861A4 true EP0528861A4 (en) 1993-07-28

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EP (1) EP0528861A4 (fr)
JP (1) JPH05509295A (fr)
CA (1) CA2040510A1 (fr)
WO (1) WO1991016066A1 (fr)

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Publication number Priority date Publication date Assignee Title
US5654274A (en) * 1992-06-01 1997-08-05 Magainin Pharmaceuticals, Inc. Biologically active peptides having N-terminal substitutions
US6348445B1 (en) 1992-06-01 2002-02-19 Magainin Pharmaceuticals, Inc. Biologically active peptides with reduced toxicity in animals and a method for preparing same
US5593866A (en) * 1992-08-21 1997-01-14 The University Of British Columbia Cationic peptides and method for production
US5607914A (en) * 1993-01-13 1997-03-04 Pioneer Hi-Bred International, Inc. Synthetic antimicrobial peptides
US6057291A (en) 1995-06-02 2000-05-02 University Of British Columbia Antimicrobial cationic peptides
CA2230160A1 (fr) 1995-08-23 1997-03-06 The University Of British Columbia Peptides cationiques antimicrobiens et procedes de reconnaissance de ceux-ci
AU730307B2 (en) * 1995-11-14 2001-03-01 Xoma Corporation Bactericidal permeability increasing protein (BPI) for treating conditions associated with corneal injury
GB9817224D0 (en) * 1998-08-08 1998-10-07 Univ Nottingham Ocular surface infection

Citations (1)

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

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Publication number Priority date Publication date Assignee Title
US4507230A (en) * 1982-05-12 1985-03-26 Research Corporation Peptide synthesis reagents and method of use

Patent Citations (1)

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

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WO1991016066A1 (fr) 1991-10-31
CA2040510A1 (fr) 1991-10-24
JPH05509295A (ja) 1993-12-22
EP0528861A1 (fr) 1993-03-03

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