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WO1991012015A1 - Peptides amphiphiles biologiquement actifs et procede pour inhiber la croissance de cellules cibles, de virus ou de cellules contaminees par virus - Google Patents

Peptides amphiphiles biologiquement actifs et procede pour inhiber la croissance de cellules cibles, de virus ou de cellules contaminees par virus Download PDF

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Publication number
WO1991012015A1
WO1991012015A1 PCT/US1991/000725 US9100725W WO9112015A1 WO 1991012015 A1 WO1991012015 A1 WO 1991012015A1 US 9100725 W US9100725 W US 9100725W WO 9112015 A1 WO9112015 A1 WO 9112015A1
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WIPO (PCT)
Prior art keywords
peptide
ala
lys
seq
lle
Prior art date
Application number
PCT/US1991/000725
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English (en)
Inventor
Barry Berkowitz
W. Lee Maloy
U. Prasad Kari
Original Assignee
Magainin Sciences 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 Sciences Inc. filed Critical Magainin Sciences Inc.
Priority to JP3504910A priority Critical patent/JPH07504152A/ja
Publication of WO1991012015A1 publication Critical patent/WO1991012015A1/fr

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Classifications

    • 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
    • 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
    • A61P31/10—Antimycotics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Thi s invention relates to biologically active peptides , and more particularly to novel biologically active peptides and uses therefor .
  • a biologically active amphiphilic peptide which includes one of the following basic structures X 1 through X 7 wherein :
  • X 2 is -[R 2 -R 2 -R 3 -R 1 -R 2 -R 2 -R 1 ]- n ;
  • X 3 is -[R 2 -R 3 -R 1 -R 2 -R 2 -R 2 -R 2 ]- n ;
  • X 4 is -[R 3- R 1 -R 2 -R 2 -R 1 -R 2 -R 2 ]- n ;
  • X 5 is -[R 1- R 2 -R 2 -R 1 -R 2 -R 2 -R 3 ]- n ;
  • X 6 is -[R 2 -R 2 -R 3 -R 1 -R 2 -R 2 -R 1 ]- n ;
  • X 7 is -[R 2- R 1 -R 2 -R 2 -R 3 -R 1 -R 2 ]- n ;
  • R 1 is a basic hydrophilic amino acid
  • R 2 is a hydrophobic amino acid
  • R 3 is a neutral hydrophilic or hydrophobic amino acid
  • n is from 2 to 5 .
  • the basic hydrophilic amino acids include , but are not limited to Lys , Arg, His , Orn, homoarginine (Har ) , 2 , 4-diamino butyric acid (Dbu ) , and p-aminophenylalanine .
  • the hydrophobic amino acids include, but are not limited to Ala, Cys, Phe, Gly, lie, Leu, Met, Pro, Val, Trp, Tyr, norleucine (Nle), norvaline (Nva), and cyclohexylalanine (Cha).
  • the neutral hydrophilic amino acids include, but are not limited to Asn, Gin, Ser and Thr.
  • the peptide when the peptide includes the structure X 1 , the peptide may include the following
  • the peptide when the peptide includes the structure X 1 , the peptide may include the following structure:
  • the peptide may include the following structure:
  • the peptide may include the following structure:
  • the peptide may include the followin g structure:
  • the peptide may include the following structure:
  • the peptide when the peptide includes the structure X 3 , the peptide may include the following structure:
  • the peptide when the peptide includes the structure X 3 , the peptide may include the following structure :
  • X 3 - Z 3 wherein X 3 is as hereinabove described, and Z 3 is: (i) R 2 ;
  • the peptide may include the following structure:
  • the peptide when the peptide includes the structure X 4 , the peptide may include the following structure:
  • the peptide when the peptide includes the structure X 4 , the peptide may include the following structure:
  • the peptide may include the following structure: (Y 4 ) a - X 4 (Z 4 ) b , wherein X 4 and Z 4 are as previously defined, a is 0 or 1, and b is 0 or 1.
  • the peptide when the peptide includes the structure X 5 , the peptide may include the following structure:
  • the peptide when the peptide includes structure X 5 , the peptide may include the following structure:
  • the peptide may include the following structure:
  • the peptide when the peptide includes the structure X 6 , the peptide may include the following structure:
  • the peptide when the peptide includes the structure X 6 , the peptide may include the following structure:
  • the peptide may include the following structure:
  • the peptide when the peptide includes the structure X 7 , the peptide may include the structure Y 7 -X 7 , wherein X 7 is as hereinabove described, and Y 7 is:
  • the peptide when the peptide includes the structure X 7 , the peptide may include the following structure:
  • the peptide may include the following structure:
  • the peptides and/or analogues or derivatives thereof may be C-terminal acids or amides.
  • n 3
  • the peptide is of one of the following structures listed below and also listed in the accompanying sequence listing:
  • a biologically active amphiphilic peptide which includes the following basic structure X 14 :
  • R 1 , R 2 , and R 3 are as hereinabove described, and R 4 is a basic hydrophilic or hydrophobic amino acid.
  • the peptide may include the following structure:
  • Y 14 -X 14 wherein X 14 is as hereinabove described, and Y 14 is: (i) R 2 ;
  • the peptide may include the following structure:
  • a is 0 or 1
  • b is 0 or 1.
  • the peptide has the following structural formula as indicated in the accompanying sequence listing:
  • 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
  • the peptide has one of the following structural formulae as indicated in the
  • n is from 2 to 5.
  • n is 3, and the peptide has the following structural formula:
  • each of the amino acid residues contained in the peptides is a D-amino acid residue or glycine.
  • all of the amino acid residues are either D-amino acid or glycine residues or L-amino acid or glycine residues.
  • amphiphilic peptide is a peptide which includes both hydrophobic and hydrophilic peptide regions.
  • the peptides hereinabove described, and/or analogues or derivatives thereof are generally water soluble to a concentration of at least 20 mg/ml at neutral pH in water.
  • such peptides are non-nemolytic; 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.
  • the peptides and/or analogues or derivatives thereof may be administered to a host; for example a human or non-human animal, in an amount effective to inhibit growth of a target cell, virus, or virally-infected cell.
  • a host for example a human or non-human animal
  • the peptides and/or analogues or derivatives thereof may be used as antimicrobial agents, anti-viral agents, antibiotics, anti-tumor agents, antiparasitic agents, antifungal agents, spermicides, as well as exhibiting other bioactive functions.
  • antimicrobial means that the peptides of the present invention inhibit, prevent, or destroy the growth or proliferation of microbes such as bacteria, fungi, or the like.
  • antibiotic means that the peptides 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
  • spermicidal as used herein means that the peptides employed in the present invention, inhibit, prevent, or destroy the motility of sperm.
  • antiviral means that the peptides 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 peptide inhibits the growth of or destroys tumors.
  • antifungal means that the peptides of the present invention may be used to inhibit the growth of or destroy fungi.
  • antiparasitic means that the peptides of the present invention may be used to inhibit the growth of or destroy parasites.
  • the peptides may be administered in vivo or in vitro.
  • the peptides also may be administered directly to a target cell, virus, or virally-ihfected cell, or the peptides may be
  • the peptides 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 parasites.
  • the peptides of the present invention allow a method for treating or controlling microbial infection caused by organisms which are sensitive to the peptides. 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.
  • antibiotics because of the antibiotic, antimicrobial, and antiviral properties of the peptides, they may also be used as preservatives or sterilants of materials susceptible to microbial or viral contamination.
  • the peptide and/or derivatives or analogues 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.
  • 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 compositions may also be used in combination with
  • the peptide(s) of the present invention may be administered to a host; in particular an animal, in an effective antibiotic and/or anti-tumor and/or anti-viral and/or anti-microbial and/or anti-parasitic and/or an ahtispermicidal amount.
  • composition in accordance with the invention will contain an effective anti-microbial amount and/or an effective antispermicidal amount and/or an effective
  • the peptide 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 would healing process.
  • peptides increase wound breaking strength.
  • the peptides of the present invention may also be employed so as to reverse the inhibition of wound healing caused by steroids such as cortisone or by conditions which compromise or depress the immune system.
  • the peptides 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 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 are also useful in the prevention or treatment of eye infections.
  • infections may be caused by bacteria such as, but not limited to, P. aeruqinosa, S. aureus, and N. gonorrhoeae, by fungi such as but not limited to C. albicans and A. fumiqatus, by parasites such as but not limited to A.
  • the peptides 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, and A. fumiqatus, which forms spores as well.
  • the peptides may also be administered to plants in an effective antimicrobial or antiviral or antiparasitic amount to prevent or treat microbial or viral or parasitic contamination thereof.
  • the peptide is employed to provide peptide dosages of from 0.1 mg. to 500 mg. per kilogram of host weight, when administered systemically. When administered topically, the peptide is used in a concentration of from .05% to 10%.
  • the peptides may be produced by known techniques and
  • the peptides may be synthesized on an automatic peptide synthesizer. Journal of the American Chemical Society, Vol. 85, pgs. 2149-54 (1963). It is also possible to produce such peptides by genetic
  • the peptides of the present invention may be employed in combination with a toxic ion for the purposes hereinabove described.
  • a toxic ion is one which when introduced into a target cell virus, or virally-infected call, inhibits and/or prevents and/or destroys the growth of the target cell, virus, or
  • Such a toxic ion 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 membrane, in sufficient amounts to affect a cell adversely.
  • the peptide and toxic ion 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 toxic ion.
  • toxic ions there may be mentioned fluoride, peroxide, bicarbonate, and silver ions.
  • the peptide and the toxic ion 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 toxic ion is effective to reduce the minimum effective concentration of the peptide for inhibiting growth of a target cell, virus, or virally-infected cell.
  • the toxic ion 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 dosages may be within the ranges hereinabove described.
  • the peptide and toxic ion may be delivered or administered in different forms; for example, the toxic 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 toxic ion delivered in an amount of about 50mM (about 0.1%).
  • the toxic ion in the form of a salt such as sodium fluoride, could be administered orally in conjunction with systemic administration of the peptide.
  • the peptide may be administered IV or IP to achieve a serum dose of 100 micrograms per milliliter (10 milligrams per kilogram) in conjunction with an oral dose of toxic ion, in particular, sodium fluoride, of 10 meq per kilogram.
  • the peptides 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,
  • the bacitracins gramacidin, polymyxin, vancomycin,
  • teichoplanin and derivatives and analogues thereof, are a group of polypeptide antibiotics.
  • a preferred bacitracin is bacitracin A.
  • Aminoglycosid ⁇ antibiotics include tobramycin, kanamycin, amikacin, the gentamicins (e.g., gentamicin C 1 , gentamicin C 2 , gentamicin C 1a ), n ⁇ tilmicin, kanamycin, and 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
  • dicloxacillin dicloxacillin, .flucloxacillin, amoxicillin, and amidinocillin.
  • 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, clarithromycm, etc.; 9-N-alkyl derivatives of erythromycin; midecamycin acetate; azithromycin; flurithromycin; rifabutin; rokitamycin, a
  • CGP-279353 (Ciba-Geigy); an erythromycin A derivative with a cyclic carbamate fused to the C 11 /C 12 position of a macrolide ring known as A-62514 (Abbott); AC-7230 (Toyo Jozo);
  • rifamycin carbenicillin, and nafcillin may be employed as well.
  • 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 and antibiotic may be adminstered by direct administration to a target ceil or by systemic or topical administration to a host which includes the target cell, in order to prevent, destroy or inhibit the growth of a target cell.
  • 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 concetration 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 dosages may be those as hereinabove described.
  • the peptide could be admnistered 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 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-protozoan agents.
  • specific anti-parasitic agents which may be employed include, but are not limited to, pentamidine isethionate, and propamidine isethionate (Brolene).
  • Anti-fungal agents which may be employed include, but are not limited to, ketoconazole. It is also to be understood that certain anti-parasitic agents may also have anti-fungal activity, and that certain anti-fungal agents may have anti-parasitic activity.
  • the peptides 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.
  • the peptides of the present invention may be administered for the purpose hereinabove described in combination with other biologically active
  • amphiphilic peptides or in combination with ion channel-forming proteins.
  • biologically active amphiphilic peptides which may be employed in combination with the peptides of the present invention include magainin peptides, PGLa peptides, XPF peptides, CPF peptides, cecropins and sarcotoxins.
  • a magainin peptide is either a magainin such as magainin I, II, or III or an analogue or derivative thereof.
  • the magainin peptides generally include at least fourteen amino acids.
  • a magainin peptide preferably has 22 or 23 amino acids.
  • Magainin peptides are described in Proc. Natl. Acad. Sci., Vol. 84, pgs. 5449-53 (Aug. 87).
  • magainin peptides refers to the magainin peptides as well as
  • derivatives and analogues thereof including but not limited to the representative derivatives and analogues.
  • a PGLa peptide is either PGLa or an analogue or derivative thereof.
  • the PGLa peptides generally include at least seventeen amino acids and may include as many as forty amino acids.
  • An XPF peptide is either XPF or an analogue or derivative thereof.
  • the XPF peptides generally include at least nineteen amino acids and may include up to forty amino acids.
  • PGLa and XPF peptides there may be mentioned the following peptide sequences as well as appropriate analogues and derivatives thereof:
  • a CPF peptide is either a CPF peptide or an analogue or derivative thereof. In general, a CPF peptide does not include more than 40 amino acids.
  • 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
  • sarcotoxins includes the basic materials as well as analogues and derivatives thereof.
  • the sarcotoxins and analogues and derivatives thereof are described in Molecular Entomology, pages 369-78, in particular page 375, Alan R. liss, Inc. (1987), which is hereby incorporated by reference.
  • Ion channel-forming proteins or peptides which may be employed in combination with the peptides of the present
  • 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.
  • Deferisins are described in Selsted, et al., J. Clin. Invest., Vol. 76, pgs. 1436-1439
  • MBP proteins are described in Wasmoen, et al., J. Biol. Chem., Vol. 263, pgs 12559-12563. (1988).
  • BPI proteins are described in Ooi, et al, J. Biol. Chem., Vol. 262, pgs.
  • ion channel-forming proteins includes the basic structures of the ion-forming proteins as well as analogues and derivatives.
  • Stock solutions of the following Peptides (SEQ ID NO: 1) through (SEQ ID NO: 64) in accordance with the present invention are prepared at a concentration of 512 ⁇ g/ml in sterile deionized distilled water and stored at -70°C.
  • Peptide (1A) is of the same structural formula as Peptide (SEQ ID NO: 1), except that each amino acid residue is a D-amino acid residue.
  • the stock peptide solution is diluted in serial dilutions (1:2) down the wells of a microtiter plate so that the final concentrations of peptides in the wells are 0.25, 0.50, 1, 2, 4, 8, 16, 32, 64, 128, and 256 ⁇ g/ml.
  • 1-5 X 10 5 CFUs/ml of either S. aureus ATCC 25923, E. coli ATCC 25922, or P. aeruqinosa ATCC 27853 were added to the wells in full strength Mueller Hinton broth (BBL 11443) from a mid-log culture.
  • the inoculum is standarized spectrophotometrically at 600nm and is verified by colony counts.
  • MIC minimal inhibitory concentration
  • S is the MIC of the peptide against S. aureus
  • P is the MIC of the peptide against P. aeruqinosa
  • E is the MIC of the peptide against
  • proteose-peptone 0.5% yeast extract; 0.5% glucose; pH 7.2.
  • Minimum Inhibitory Concentration (MIC) and Minimum Amoebicidal Concentration (MAC) of the trophozoites the contents of appropriate flasks were centrifuged, washed free of "old" medium and peptide with dilute saline, resuspended in fresh ppyg medium, and transferred to Corning tissue culture tubes (16 X 125mm). The tubes were incubated at 30°C and examined at daily intervals for growth of amoebas. Minimum Amoebicidal Concentration is defined is the minimum concentration of peptide necessary to kill the trophozoites. The results are given in Table II below. TABLE II
  • peptides of the present invention whether administered alone or in combination with agents such as toxic ions,
  • antibotics or other biologically active peptides or proteins as hereinabove described, 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.
  • peptide 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, parasites, fungi, and the like.
  • the peptide may be administerd 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.
  • the peptides may be administerd either alone or in combination with a toxic ion, antibiotic, or ion channel forming peptide or protein as
  • the peptide When the peptide is administered in combination with a toxic ion, the activity of the peptide is potentiated.
  • the peptide When the peptide is administered in combination with an agent as hereinabove described, it is possible to administer the peptide and agent in separate forms.
  • the agent may be administered systemically and the peptide may be administered topically.
  • the peptide When the peptide is adminitered 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.
  • water-soluble vehicles which may be employed include, but are not limited to, glycols, such as polyethylene glycol, hydroxycellulose, and KY Jelly.
  • the water-soluble vehicle is preferably free of an oily substance.
  • the peptide may also be employed in combination with a toxic ion as hereinabove described in the form of an oral composition for oral hygiene.
  • 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.
  • Such composition may thus be used to treat or prevent periodontal disease, to prevent or reduce plaque, and/or to prevent or treat or reduce dental caries.
  • the peptide and toxic ion may be used to inhibit, prevent, or destroy the growth of Streptococcus mutans, which is associated with dental caries and periodontal disease.
  • ADDRESSEE Carella, Byrne, Bain, Gilfillan,

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Abstract

Est décrit un peptide amphiphile biologiquement actif qui, selon l'aspect de la présente invention, comporte une des structures de base suivante X1 à X7, où: X1 est [R1-R2-R2-R3-R1-R2-R2]-n; X2 est -[R2-R2-R3-R1-R2-R2-R1]-n; X3 est -[R2-R3-R1-R2-R2-R1-R2]-n; X4 est -[R3-R1-R2-R2-R1-R2-R2]-n; X5 est -[R1-R2-R2-R1-R2-R2-R3]-n; X6 est -[R2-R2-R1-R2-R2-R3-R1]-n; et X7 est -[R2-R1-R2-R2-R3-R1-R2]-n; où R1 est un aminoacide hydrophile basique, R2 est un aminoacide hydrophobe, R3 est un aminoacide hydrophile neutre, hydrophile basique ou hydrophobe et n vaut de 2 à 5. Ces compositions peptidiques s'utilisent pour inhiber la croissance d'une cellule cible, d'un virus ou d'une cellule contaminée par virus.
PCT/US1991/000725 1990-02-08 1991-02-04 Peptides amphiphiles biologiquement actifs et procede pour inhiber la croissance de cellules cibles, de virus ou de cellules contaminees par virus WO1991012015A1 (fr)

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US476,629 1990-02-08

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EP (1) EP0514464A4 (fr)
JP (1) JPH07504152A (fr)
CA (1) CA2035959A1 (fr)
WO (1) WO1991012015A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0533795A1 (fr) * 1990-05-14 1993-03-31 Magainin Pharmaceuticals, Inc. Composition et traitement utilisant des peptides biologiquement actifs contenant des resites d'aminoacides d
WO1993024138A1 (fr) * 1992-06-01 1993-12-09 Magainin Pharmaceuticals, Inc. Peptides biologiquement actifs presentant des substitutions n-terminales
WO1994009810A1 (fr) * 1992-10-26 1994-05-11 Magainin Pharmaceuticals, Inc. Nouveaux peptides a activite biologique et leurs applications
WO1995019370A1 (fr) * 1994-01-18 1995-07-20 Magainin Pharmaceuticals Inc. Peptides amphiphiliques formant des canaux ioniques et presentant des modifications n-terminales
EP0671930A1 (fr) * 1991-07-25 1995-09-20 Magainin Pharmaceuticals Inc. Propylaxie et traitement d'affections bucco-dentaires a l'aide de peptides biologiquement actifs
WO1996028468A2 (fr) * 1995-03-09 1996-09-19 Unilever Plc Peptides amphiphiles et analogues desdits peptides
US5593866A (en) * 1992-08-21 1997-01-14 The University Of British Columbia Cationic peptides and method for production
US5622964A (en) * 1992-10-20 1997-04-22 Zeneca Limited Heterocyclic derivatives
US5654274A (en) * 1992-06-01 1997-08-05 Magainin Pharmaceuticals, Inc. Biologically active peptides having N-terminal substitutions
US6191254B1 (en) 1995-08-23 2001-02-20 University Of British Columbia Antimicrobial cationic peptides
US6297215B1 (en) 1995-06-02 2001-10-02 The University Of British Columbia Antimicrobial cationic peptides
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
US8318899B2 (en) 2008-01-24 2012-11-27 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Lytic domain fusion constructs and methods of making and using same
US9492563B2 (en) 2012-10-30 2016-11-15 Esperance Pharmaceuticals, Inc. Antibody/drug conjugates and methods of use
US11001613B2 (en) * 2008-12-19 2021-05-11 Takeda Pharmaceutical Company Limited TFPI inhibitors and methods of use

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US4659692A (en) * 1982-11-19 1987-04-21 The Regents Of The University Of California Cationic oligopeptides having microbicidal activity
US4636489A (en) * 1983-07-07 1987-01-13 Plantorganwerk Kg Modified protease inhibitors, process for their preparation, and pharmaceutical compositions prepared therefrom
US4617149A (en) * 1983-09-21 1986-10-14 Eli Lilly And Company Growth hormone release factor analogs
US4668662A (en) * 1984-04-18 1987-05-26 Hoechst Aktiengesellschaft Polypeptides with an anticoagulant action, a process to prepare or obtain them, their use and agents containing them
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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0533795A4 (en) * 1990-05-14 1993-10-20 Magainin Sciences, Inc. Composition of and treatment with biologically active peptides having d-amino acid residues
EP0533795A1 (fr) * 1990-05-14 1993-03-31 Magainin Pharmaceuticals, Inc. Composition et traitement utilisant des peptides biologiquement actifs contenant des resites d'aminoacides d
EP0671930A1 (fr) * 1991-07-25 1995-09-20 Magainin Pharmaceuticals Inc. Propylaxie et traitement d'affections bucco-dentaires a l'aide de peptides biologiquement actifs
EP0671930A4 (fr) * 1991-07-25 1996-02-07 Magainin Pharma Propylaxie et traitement d'affections bucco-dentaires a l'aide de peptides biologiquement actifs.
US5654274A (en) * 1992-06-01 1997-08-05 Magainin Pharmaceuticals, Inc. Biologically active peptides having N-terminal substitutions
WO1993024138A1 (fr) * 1992-06-01 1993-12-09 Magainin Pharmaceuticals, Inc. Peptides biologiquement actifs presentant des substitutions n-terminales
US5686563A (en) * 1992-06-01 1997-11-11 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
US5622964A (en) * 1992-10-20 1997-04-22 Zeneca Limited Heterocyclic derivatives
US5424290A (en) * 1992-10-26 1995-06-13 Magainin Pharmaceuticals Inc. Biologically active peptides and uses therefor
WO1994009810A1 (fr) * 1992-10-26 1994-05-11 Magainin Pharmaceuticals, Inc. Nouveaux peptides a activite biologique et leurs applications
WO1995019370A1 (fr) * 1994-01-18 1995-07-20 Magainin Pharmaceuticals Inc. Peptides amphiphiliques formant des canaux ioniques et presentant des modifications n-terminales
WO1996028468A2 (fr) * 1995-03-09 1996-09-19 Unilever Plc Peptides amphiphiles et analogues desdits peptides
WO1996028468A3 (fr) * 1995-03-09 1997-04-17 Unilever Plc Peptides amphiphiles et analogues desdits peptides
US6297215B1 (en) 1995-06-02 2001-10-02 The University Of British Columbia Antimicrobial cationic peptides
US6465429B1 (en) 1995-06-02 2002-10-15 The University Of British Columbia Antimicrobial cationic peptides
US6906035B2 (en) 1995-06-02 2005-06-14 The University Of British Columbia Antimicrobial cationic peptides
US6191254B1 (en) 1995-08-23 2001-02-20 University Of British Columbia Antimicrobial cationic peptides
US7390873B2 (en) * 1995-08-23 2008-06-24 University Of British Columbia Antimicrobial cationic peptides
US8318899B2 (en) 2008-01-24 2012-11-27 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Lytic domain fusion constructs and methods of making and using same
US8546535B2 (en) 2008-01-24 2013-10-01 Esperance Pharmaceuticals, Inc. Lytic domain fusion constructs and methods of making and using same
US9255134B2 (en) 2008-01-24 2016-02-09 Esperance Pharmaceuticals, Inc. Lytic domain fusion constructs and methods of making and using same
US11001613B2 (en) * 2008-12-19 2021-05-11 Takeda Pharmaceutical Company Limited TFPI inhibitors and methods of use
US9492563B2 (en) 2012-10-30 2016-11-15 Esperance Pharmaceuticals, Inc. Antibody/drug conjugates and methods of use
US10233214B2 (en) 2012-10-30 2019-03-19 Esperance Pharmaceuticals, Inc. Antibody/drug conjugates and methods of use

Also Published As

Publication number Publication date
JPH07504152A (ja) 1995-05-11
EP0514464A4 (en) 1993-04-28
CA2035959A1 (fr) 1991-08-09
EP0514464A1 (fr) 1992-11-25

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