CA2007913A1 - Composition and treatment with peptide combinations - Google Patents

Composition and treatment with peptide combinations

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Publication number
CA2007913A1
CA2007913A1 CA 2007913 CA2007913A CA2007913A1 CA 2007913 A1 CA2007913 A1 CA 2007913A1 CA 2007913 CA2007913 CA 2007913 CA 2007913 A CA2007913 A CA 2007913A CA 2007913 A1 CA2007913 A1 CA 2007913A1
Authority
CA
Canada
Prior art keywords
peptide
derivative
analogue
process
administered
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.)
Abandoned
Application number
CA 2007913
Other languages
French (fr)
Inventor
Michael Zasloff
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.)
CHILDREN'S HOSPITAL OF PHILDELPHIA
Original Assignee
Michael Zasloff
Magainin Sciences Inc.
Magainin Pharmaceuticals, Inc.
Children's Hospital Of Phildelphia The
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
Priority to US30298589A priority Critical
Priority to US302,985 priority
Priority to US34689489A priority
Priority to US346,894 priority
Application filed by Michael Zasloff, Magainin Sciences Inc., Magainin Pharmaceuticals, Inc., Children's Hospital Of Phildelphia The filed Critical Michael Zasloff
Publication of CA2007913A1 publication Critical patent/CA2007913A1/en
Application status is Abandoned legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates

Abstract

ABSTRACT OF THE DISCLOSURE
A composition comprising a magainin peptide or an analogue or derivative thereof, and at least one member selected from the group consisting of a PGLa peptide or analogue or derivative thereof, and an XPF
peptide or analogue or derivative thereof. The composition is employed as a pharmaceutical.

Description

COMPOSITION ~ND TREATMENT WITH
PEPTlDe CGM~INATION5 Thi~ invention relate3 to biologically active peptides, and more particularly to compositions and uses involving combinations of biologically active peptides.
In accordance with an a~pect of the present invention, there iq provided a composition which includes (a) a magainin peptide OE analogue or derivative thereof; and (b) at least one member selected from the group consisting of (i) a PGLa peptide or analogue or derivative thereof and (ii) an XPF peptide or analogue or derivative thereof. The magainin peptide or analogue or derivative thereof, as well as the PGLa peptide or analogue or derivative thereof and the ~PF peptide or analogue or derivative thereof, may be amide terminated or carboxy-terminated.
In accordance with another aspect of the present invention, there is provided a process which compri~Ps admini~terin~ to a ho~t both (a) a magainin peptide or analogue or derivative thereof and (b) at lea3t one member selected from the group con~i~ting of (i) ~n XPF peptide or analogue or derivative th~reof and (ii) a PGLa peptide or analogue or derivative thereof. In one embodiment, components (a) and (b) may be administered in separate compositions. In a~o~her embodiment, components (a) and (b) may be administered in a single composition.
In addition, compone~lts (a) and (b) may b~
administered in amoun~s effective to inhibit gro~th of a target.
Although the present invention is not to be limited by any theoretical reasoning, it is believed that the combination of the magainin peptide with the PCLa peptide or XPF peptide provide~ a syner~istic effect in the inhibition of growth of a target. The target, for example, may be bacteria, fungi~
protozoa, virally infected cells, malignant cells, or sperm cells as compared to normal host cells. The synergi~m may be due to association of the peptides to a novel multimeric complex, such as a dimer, which possesses markedly increased membrane affinity for the target cells. The complex formed between the two peptides is believed to possess potent membrane disruptive properties. It is believed that the peptides have the capacity to organize within tar~et cell membranes and to disturb cellular functions.
In ~eneral, the magainin peptide or analogue or derivative thereof is employed in a dosage of from about lmg to about lOOmg per kilogram of host weight, when administered systemioally. When administered topically, the magainin peptide is used in a concentration of from about .05% to about . 50%.
The PGLa peptide or analogue or derivative thereof, when administered 5y~temically, is adminis~ered in a dosage o~ from about lmg to about lOOmg per kilogram of host weight. When administered ~ 7~L3 topically, the PGLa peptide is administered in a concentration of from about 0.5% to about .50~.
The ~PF pep~ide or analogue or derivative thereof, when administered systemically, is administered in a dosage of from about lmg to ~bout lOOmg per kilogram of ho~t weight. When administered topically, the XPF peptide or analogu~ or derivative thereof is admi~ister~d in a concentration of from about .05% to about .50%.
The use of this combination of peptides in accordance with the present invention is effective as an antibiotic, and may be employed to inhibit, prevent or destroy the growth or proliferation of microbesl such as bacteria, fungi, viruses or the like. Similarly, such compositions may be employed as an an~i-viral composition to inhibit, prevent or destroy the growth or proliferation of viruses.
Such compositions may also be employed as a spermicide to inhibit, prevent or destroy the motility of sperm.
Such compositions may also be employed as anti-tumor agents to in~ibit the growth of or destroy tumors.
The compo~itions 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.
Such compositions may be employed for treating or controlling microbial infection caused by organisms which are sensitive to ~uch composition. The treatment may comprise admini~terin~ to a host organism or tissue~ acceptable to or affiliated with a microbial infection an anti-microbial amount of magainin peptide or analog or derivative thereof and of PGLa peptide or XPF peptide.

~7~

Th~ compositions may also be used as preservatives or sterilants for materials susceptible to microbial contamination.
The magainin peptide may be, for example, 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 X12 11 11 12 R13 Rll R14 ~R12 ~Rll ~
14 12 11 11 11 ~14a (R15)n ~~14a -R14 ~~
wherein R11 is a hydrophobic amino acid, R12 is a basic hydrophilic amino acid; R13 is a hydrophobic, neutral hydrophilic or basic hydrophilic amino acid;
R14 and R14a are hydrophobic or basic hydrophilic amino acids; R15 is glutamic or aspartic acid, or a hydrophobic or basic hydrophilic amino acid, and n is O or 1. In a preferred embodi~ent, R13 is a hydrophobic or neutral hydrophilic amino acid, R14a is a hydrophobic amino acid, and R15 is glutamic acid or aspartic acid.
The hydrophobic amino acids may be selected from the class consisting of Ala, Cys, Phe, Gly, Ile, Leu, Met, Val, Trp, and Tyr. The neutral hydrophilic amino acids may be selected from the class consisting of Asn, Gln, Ser, and Thr. The basic hydrophilic amino acids may be selected from the class consisting of Lys, Arg, and His, and ornithine (O).
The.magainin peptides generally include at least seventeen amino acids and may also include up to forty amino acids. Accordingly, the hereinabove described basic peptide structure of a magainin peptide may include additional amino acids at the amino end or at the carboxyl end, or at both ends.
Thus, for example, a magainin peptide may include the following structure:

~7~L3 -Y12 -Xl -where X12 is the hereinabove described basic pertide structure and Y12 is (i) Rl~
( i i ) R14 - R12 t iii ) 11 R14a R12 (iv) R14 ~Rll -R14 -R
11' R12~ R14 and R14a are as previously defined.
A magai~in pep~ide may also have the following structure wherin X12 is as preYiously defined and Z12 is:
(i) R16 where R16 i3 a basic hydrophilicamino acid or asparagine or glutamine.
(ii) R16 -R17 where R17 is a neutral hydrophilic amino acid, a hydrophobic amino acid, or a basic hydrophilic amino acid. Preferably R17 is a neutral hydrophilic amino acid.
A magainin peptide may also have the following structure:
(Y12) a-X12 (Z12)b re X12, Y12 and Z12 are as previously defined and a is O or 1 and b is O or 1.
The magainin peptides may also include the following basic peptide stmcture X13:
14 11 14a R12 Rll Rll-R12-R13-Rll R14 R12-Rll-Rll-R12- ~ wherein Rll ,R12 ,R13 . ~1 and R14a are amino acids as hereinabove described.
The magainin peptide may also include the follo~7ing structure X13-Z13; wherein X13 i~ the hereinabove described ba~ic peptide struc~ure and Z13 is (Rll)n (Rll)n (Rll)n (~14a)n (R15)n (R14a)n (R14)n (R16)n .

(R17)n wherein Rll, Rl~, R14a~ R15, R16' and R17 are as hereinabove described, and n is O or 1, and each n may be the same or dlfferent.
Th~ magainin peptides generally include at least fourteen amino acids and ~ay include up to forty amino acids. A magainin peptide preferably has 22 or 23 amino acids. Accordingly, the hereinabove described basic peptide ~tructure~ of a magainin peptide may include additional amino acids a~ the amino end or a~ the carboxyl end, or at both ends.
As representative examples of such magainin peptides, there may be mentioned peptides having the following primary sequence (expressed as a single letter code) as well as appropriate analogues and deriatives thereof:
(a) (NH2) GIGKFLHSAGKFGKAFVGEIMKS (OH) or (NH2) (Magainin I) (b) (NH2) GIGKFLHSAKKFGXAFVG~I~NS (OH) or (NH2) (Magainin II) (c) (NH2) GIGKFLHSAKKFGKAFVGEIMN (OH) or (NH2) (Magainin III) The following are examples of peptide derivative~ or analogs of the basic s~ructure:
(d)(NH2) IGKFLHSAKKFGKAFVGEIMNS (OH) or (NH2) (e)~NH2) GKFLHSAKKFGKAFVGEIMNS (OH) or (NH2) (f)(NH2) KFLHSAKKFGKAFVGEIMNS (OH) or (NH2) Magainin peptides are described in Proc. Natl.
Acad Sci. Yol 84 pp. 5449-53 ¢Aug. 87). The term "magainin peptides" as used herein refers to the basic magainin structure as well as derivatives and analogs thereof, including but not limited to the representative derivative~ or analogs.
The peptide employed in conJunction with the magainin peptide is a PGLa peptide or an XPF peptide.

;~ 3 A PGLa peptide i5 ~ither PCLa or an analogue or deriva~ive thereof. The PGLa peptides preferably include the following basic structure X14:
11 17 12 Rll ~14 R14 Rll ~
11 14 12 Rll Rll R12 -Rll -11 Rll R12 Rll' Rl2' R14~ and R17 are as previou~ly defined.
The PGLa peptides generally include at least seventeen amino acids and may include as many as forty amino acids. Accordingly, the hereinabove described basic peptide sturcture for a PGLa peptide may include additional amino acids a~ the amino end or at the carboxyl end or at both the amino and carboxyl end.
Thus, for example, a PGLa peptide may have the following sturcture:

where Xl4 is as previously defined and Y14 iS
(i) Rll;
(ii) R14 R
where Rll and R14 are as previously defined.
For example, a PGLa peptide may also have the following structure:
-Xl4 -Z14-where X14 is as previou~ly defined; and Z14 is:
(i) Rll; or (ii) Rll-Rll, where Rll i~ a~ previously defined.
A PGLa peptide may also have the following structure: (yl4)a-xl4-(z14)b re X14; Y14 and Z14 are a~ previously d~fined, a is O or 1 and b is 0 or 1.

An XPF peptide is eith~r XPF or a~ analogue or d~rivative thereof. The XPF like peptides preferably include the following basis peptide structure Xl6:
11 17 12 Rll R14 Rl8 R17-Rll-Rl4-Rl2-Rll-Rll-Rl2-11 11 11 R12 (R15)n R~
Rll ~ R12 t Rl4~ Rls and R17 are as previously defined and Rl8 is glutamine or asparagi~e, or a basic hydrophilic, or hydrophobic amino acid, and n is O or 1.
The XPF peptid2s 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.
Thus, for example, an XPF peptide may include the following struct~re:

where X16 is as previously defined and Y16 is (i) Rll or ~ ii ) R14 -Rll where R~l and R14 are as previously de~ined.
An XPF peptide may include the follwing structure:
-X16 ~ Z16 ~
where X16 is a~ previously defined and Z16 is (i) Rll; or (ii) Rll -Rl~ i or (iii) Rll -Rlg -Proline; or ( iv) Rll -R18 -Proline R12 An XPF peptide may also have the following structure:
(Y16 )a X16 ( Z16 )b 2~

~ here X16, Y16 and Z16 are as prevlously defined : a is O or 1 and b is 0 or 1.
Preferred are XPF or PGLa peptides, which are characteriæed by the following primary amino acid sequence (single letter amino aoid code);
PGLa: GMASKAGAIAGKIAKVALKAL (NH2) XPF: GWASKIGQTLGKIAKVGLKELIQPK
A re~iew of XPF and PGLa can be found in Hof~man et al, EMBO J. 2:711-714, 1983; Andreu et al, J.
Biochem. 149:531-535, 1985; Gibson e~ al J. Biol.
Chem. 261:5341-5349, 1986; and Giovanni et al, Biochem J. 241:113-120, 19&7.
The present invention will be further described with re~pect to the following examples, however, the scope of the present invention is not to be limited thereby.

About 105 bacteria/ml were added to a small volume of Luria broth. Magainin 2 (MGN2), PGLa peptidej or a mixture of MGN2 and PGLa in a 1:1 molar ratio was added to the broth in increasing concentration. The minimal inhibitory concentration (MIC), which inhibits microbial growth completely at 24 hours i~ noted below in Table 1.

~J7~3 TA~LE 1 ANTIBACTERXAL ACTIVITY OF ~OMBINATION OF PGLa AND
~AGAININ 2 ORGANISM MINIMAL INHIBITORY CONCENTRATION (~
~GN2 PGLa PGLa/MGN2 (1:1 molar ratio) S. aureus >500 >500 10 P. ~eruginosa 250 250 10 C. albicans 250 240 10 Micrococcus 125 125 10 Diphtheroids125 125 10 E. coli 50 50 10 The above result~ indicate an increase in antibacterial activity when a combination of Magainin 2 and PGLa peptides is added to a culture bro~h of bacteria in a 1:1 molar ratio of Magainin 2 to PGLa over either peptide added alone.

In this example, the concentration of S. aureus killed by 100 ~g/ml of preparations of Magainin 2, PGLa, and a preparation of Magainin 2 and PGLa in a 1:1 molar ratio is noted. It was found that a 100 ~g/ml preparation of Magainin 2 does not completely ~ill S. aureus at concentrationq of bacteria at less than 10 bacterial/ml. Similar re~ults were also obtained for PGLa. The 100 yg/ml preparation of the equimolar miture of Magainin 2 and PGLa, however, achieved complete killi~g o~ a concentration of 105 bacteria/ml. Thus, the equimolar mixture of Magainin ~ ;37~3 2 and PGLa achiev~d an inc~ea~e in bac~ericidal potency over either peptide by greater than 105.

Approximately 103 S. aureus bacteria were added per/ml of Luria broth. Peptid~ preparations con~aining varying molar ratio amounts of PGLa to Magainin 2 (mole PGLa/mole MGN2) were added to the broths to increasing concentration of peptide (~g/ml). The microbial inhibitory concentration (MIC), at which point no growth was evid~nt after 24 hours was measured for each peptide preparation. The results are given in Table 2 below.

Mole PGLa/
Mole MGN2~IC v~. S. aureus (~g/ml) lO/0 >500 10/ 1 ~$
7.5/2.5 15 5/5 a 2.5/7.5 15 0/lO >500 The above results indicate that maximum bactericital activity is achieved when an equimolar mixture of PGLa and Magainin 2 is added to the S.
aureus culture. It is also shown, however, that preparations containing both peptides in any molar ratio achieved greater bactericidal activity than either peptide alone.
The peptide combinatio~s, in acoordance wlth the present invention, may be employed for 'creating a wide variety of hosts. In accordance ~ith a preferred embodiment, a host may be an animal, and such animal may be a human or non-human animal. The magainin peptide and the PGLa and/or XPF peptide may b¢ employed together in a single composition, or in ~eparate compositions.
The magainin peptide and PGLa and/or XPF peptide may be employed in a wide variety of pharmaceutical compositions in combination wi~h 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 msy be in any suitable form such as a liquld, solid, semi-solid, injectable solution, tablet, ointmen~, lotion, paste, capsule, or the like. It i~ also contemplated that the magainin peptide and the PGLa and/or XPF peptide may be delivered or administered in different form~. The magainin peptide and PGLa and/or XPF peptide may also be used in combination with ad~uvants, protease inhibitors, or compatible drugs where such a combination is seen to be desirable or advantageous in controlling infection cau~ed by harmful microorganisms including protozoa viruses, and the like.
The peptidets) of the present invention may be administered to a host; in particular an animal, in an e~fective antibiotic and/or anti-tumor and/or anti-viral and/or anti-microbial and/or a spermicidal amount.
Numerous modification~ and variations of the present invention are pos~ible in light of the above teachin~s, and, therefore, within the ~cope of the accompanying claim~, the invention may be practiced other than as particularly described.

Claims (28)

1. A composition comprising:
(a) a magainin peptide or analogue or derivative thereof; and (b) at least one member selected from the group consisting of (i) a PGLa peptide or analogue or derivative thereof and (ii) an XPF peptide or analogue or derivative thereof.
2. The composition of Claim 1 wherein components (a) and (b) are present in an amount to inhibit growth of a target cell.
3. The composition of Claim 1 wherein component (b) is a PGLa peptide or analogue or derivative thereof.
4. The composition of Claim 1 wherein component (b) is an XPF peptide or analogue or derivative thereof.
5. A process, comprising:
administering to a host both (a) a magainin peptide or analogue or derivative thereof and (b) at least one member selected from the group consisting of (i) an XPF peptide or analogue or derivative thereof and (ii) a PGLa peptide or analogue or derivative thereof.
6. The process of Claim 5 wherein components (a) and (b) are administered in separate compositions.
7. The the process of Claim 5 wherein (a) and (b) are administered in a single composition.
8. The process of Claim 5 wherein (a) and (b) are administered in amounts effective to inhibit growth of a target.
9. The process of Claim 8 wherein the magainin peptide or analogue or derivative thereof is administered systemically.
10. The process of Claim 9 wherein the magainin peptide or analogue or derivative thereof is administered in an amount of from about 1mg to about 100mg per kilogram of host body weight.
11. The process of Claim 8 wherein the magainin peptide or analogue or derivative thereof is administered topically.
12. The process of Claim 11 wherein the magainin peptide or analogue or derivative thereof is administered in a concentration of from about .05% to about .50%.
13. The process of Claim 8 wherein component (b) is a PGLa peptide or analogue or derivative thereof.
14. The process of Claim 13 wherein the PGLa peptide or analogue or derivative thereof is administered systemically.
15. The process of Claim 14 wherein the PGLa peptide or analogue or derivative thereof is administered in an amount of from about ]1mg to about 100mg per kilogram of host body weight.
16. The process of Claim 13 wherein the PGLa peptide or analogue or derivative thereof is administered topically.
17. The process of Claim 16 wherein the PGLa peptide or analogue or derivative thereof is administered in a concentration of from about .05% to about .50%.
18. The process of Claim 8 wherein component (b) is an XPF peptide or analogue or derivative thereof.
19. The process of Claim 18 wherein the XPF
peptide is administered systemically.
20. The process of Claim 19 wherein the XPF
peptide or analogue or derivative thereof is administered in an amount of from about 1mg to about 100mg per kilogram of host body weight.
21. The process of Claim 18 wherein the XPF
peptide or analogue or derivative thereof is administered topically.
22. The process of Claim 21 wherein the XPF
peptide or analogue or derivative thereof is administered in a concentration of from about .05% to about .50%.
23. The process of Claim 8 wherein said target is a bacterium.
24. The process of Claim 8 wherein said target is a fungus.
25. The process of Claim 8 wherein said target is a protozoan.
26. The process of Claim 7 wherein said target is a tumor cell.
27. The process of Claim 8 wherein said target is a virally-infected cell.
28. The process of Claim 8 wherein said target is a sperm cell.
CA 2007913 1989-01-30 1990-01-17 Composition and treatment with peptide combinations Abandoned CA2007913A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US30298589A true 1989-01-30 1989-01-30
US302,985 1989-01-30
US34689489A true 1989-05-03 1989-05-03
US346,894 1989-05-03

Publications (1)

Publication Number Publication Date
CA2007913A1 true CA2007913A1 (en) 1990-07-30

Family

ID=26973198

Family Applications (1)

Application Number Title Priority Date Filing Date
CA 2007913 Abandoned CA2007913A1 (en) 1989-01-30 1990-01-17 Composition and treatment with peptide combinations

Country Status (5)

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EP (1) EP0455719A4 (en)
JP (1) JPH04506056A (en)
AU (1) AU5042890A (en)
CA (1) CA2007913A1 (en)
WO (1) WO1990008552A1 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU648140B2 (en) * 1991-02-01 1994-04-14 Virtual Drug Development, Inc. Reverse antimicrobial peptides and antimicrobial compositions
EP0590044A4 (en) * 1991-06-12 1996-06-12 Magainin Pharma Composition and treatment with biologically active peptides having c-terminal substitutions
US5593866A (en) * 1992-08-21 1997-01-14 The University Of British Columbia Cationic peptides and method for production
US6057291A (en) 1995-06-02 2000-05-02 University Of British Columbia Antimicrobial cationic peptides
CA2230160A1 (en) 1995-08-23 1997-03-06 The University Of British Columbia Antimicrobial cationic peptides and methods of screening for the same

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0362209B1 (en) * 1987-03-04 1994-06-08 THE UNITED STATES OF AMERICA as represented by the Secretary United States Department of Commerce New synthetic bioactive compounds and method of producing bioactive effect

Also Published As

Publication number Publication date
EP0455719A4 (en) 1992-07-08
JPH04506056A (en) 1992-10-22
AU5042890A (en) 1990-08-24
EP0455719A1 (en) 1991-11-13
WO1990008552A1 (en) 1990-08-09

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