EP0455719A4 - Composition and treatment with peptide combinations - Google Patents
Composition and treatment with peptide combinationsInfo
- Publication number
- EP0455719A4 EP0455719A4 EP19900902924 EP90902924A EP0455719A4 EP 0455719 A4 EP0455719 A4 EP 0455719A4 EP 19900902924 EP19900902924 EP 19900902924 EP 90902924 A EP90902924 A EP 90902924A EP 0455719 A4 EP0455719 A4 EP 0455719A4
- Authority
- EP
- European Patent Office
- Prior art keywords
- peptide
- derivative
- analogue
- administered
- pgla
- 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.)
- Withdrawn
Links
Classifications
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
Definitions
- This invention relates to biologically active peptides, and more particularly to compositions and uses involving combinations of biologically active peptides.
- a composition which includes (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.
- the magainin peptide or analogue or derivative thereof, as well as the PGLa peptide or analogue or derivative thereof and the XPF peptide or analogue or derivative thereof may be amide terminated or carboxy- erminated.
- a process which comprises 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.
- components (a) and (b) may be administered in separate compositions.
- components (a) and (b) may be administered in a single composition.
- components (a) and (b) may be administered in amounts effective to inhibit 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 synergism 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 target cell membranes and to disturb cellular functions.
- 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 systemically.
- 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 systemically, is administered in a dosage of from about lmg to about lOOmg per kilogram of host weight. When administered topically, the PGLa peptide is administered in a concentration of from about 0.5% to about .50%.
- the XPF peptide or analogue or derivative thereof when administered systemically, is administered in a dosage of from about lmg to about lOOmg per kilogram of host weight. When administered topically, the XPF peptide or analogue or derivative thereof is administered in a concentration of from about .05% to about .50%.
- 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 microbes, such as bacteria, fungi, viruses or the like. Similarly, such compositions may be employed as an anti-viral composition to inhibit, prevent or destroy the growth or proliferation of viruses.
- compositions may also be employed as a spermicide to inhibit, prevent or destroy the motility of sperm.
- compositions may also be employed as anti-tumor agents to inhibit the growth of or destroy tumors.
- compositions 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 such composition.
- the treatment may comprise administering to a host organism or tissues 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.
- the 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 X, description
- R, , is a hydrophobic amino acid
- R, 2 is a basic hydrophilic amino acid
- , is a hydrophobic, neutral hydrophilic or basic hydrophilic amino acid
- R,, and R, are hydrophobic or basic hydrophilic amino acids;
- R, 5 is glutamic or aspartic acid, or a hydrophobic or basic hydrophilic amino acid, and n is
- R, is a hydrophobic,or neutral hydrophilic amino acid
- R, is a hydrophobic amino acid
- R, 5 is glutamic acid or aspartic acid.
- the hydrophobic amino acids may be selected from the class consisting of Ala, Cys, Phe, Gly, lie, Leu, Met, Val, Trp, and Tyr.
- the neutral hydrophilic amino acids may be selected from the class consisting of Asn, Gin, Ser, and Thr.
- the basic hydrophilic amino acids may be selected from the class consisting of Lys, Arg, and His, and ornithine (0).
- 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.
- a magainin peptide may include the following structure: -Y 12 -x 12 - where , 2 is the hereinabove described basic peptide structure and Y, delete is
- a magainin peptide may also have the following structure
- R.g is a basic hydrophilic amino acid or asparagine or glutamine.
- R,g " R i 7 where R, 7 is a neutral hydrophilic amino acid, a hydrophobic amino acid, or a basic hydrophilic amino acid.
- R, 7 is a neutral hydrophilic amino acid.
- a magainin peptide may also have the following structure: where 12 , Y 1 and Z, 2 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, 3 :
- R "R ll”R 14a "R 12 "R ll “R ll “R 12 “R 13 “ ' w " ere i n H ,R 12' R 13' R 14' and R ⁇ a are amino acids as hereinabove described.
- the magainin peptide may also include the following structure X I 'Z T . wherein , is the hereinabove described basic peptide structure and Z, ⁇ is
- R ⁇ , ⁇ , 1 a , R I5 , R 16 , and R 1? are as hereinabove described, and n is 0 or 1, and each n may be the same or different.
- the magainin peptides generally include at least fourteen amino acids and may include up to forty amino acids.
- a magainin peptide preferably has 22 or 23 amino acids. Accordingly, the hereinabove described basic peptide 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 sequence (expressed as a single letter code) as well as appropriate analogues and deriatives thereof:
- the peptide employed in conjunction with the magainin peptide is 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 structure X.,:
- 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 at the amino end or at the carboxyl end or at both the amino and carboxyl end.
- a PGLa peptide may have the following sturcture:
- PGLa peptide may also have the following structure:
- a PGLa peptide may also have the following structure: ⁇ a 'X W (Z 14 J b where , 4 ; Y, 4 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 like peptides preferably include the following basis peptide structure X,lb, :
- 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 include the follwing structure:
- X 16> Y ⁇ g and Z ⁇ g 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); PGLa: GMASKAGAIAGKIAKVALKAL (NH £ ) XPF: GWASKIGQTLGKIAKVGLKELIQPK A review of XPF and PGLa can be found in Hoffman et al, EMBO J. 2:711-714, 1983; Andreu et al, J.
- EXAMPLE 1 About 10 bacteria/ml were added to a small volume of Luria broth. Magainin 2 (MGN2), PGLa peptide, 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 is noted below in Table 1.
- EXAMPLE 2 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 kill S. aureus at concentrations of bacteria at less than 10 bacterial/ml. Similar results were also obtained for PGLa. The 100 ⁇ g/ml preparation of the equimolar miture of Magainin 2 and PGLa, however, achieved complete killing of a concentration of 10 bacteria/ml. Thus, the equimolar mixture of Magainin 2 and PGLa achieved an increase in bactericidal potency over either peptide by greater than 10 .
- EXAMPLE 3 3 Approximately 10 S. aureus bacteria were added per/ml of Luria broth. Peptide preparations containing varying molar ratio amounts of PGLa to
- Magainin 2 (mole PGLa/mole MGN2) were added to the broths to increasing concentration of peptide
- peptide combinations in accordance with the present invention, may be employed for treating a wide variety of hosts.
- 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 be employed together in a single composition, or in separate compositions.
- the magainin peptide and PGLa and/or XPF peptide 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. It is also contemplated that the magainin peptide and the PGLa and/or XPF peptide may be delivered or administered in different forms.
- the magainin peptide and PGLa and/or XPF peptide 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.
- the ⁇ eptide(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 a spermicidal amount.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Marine Sciences & Fisheries (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Immunology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US30298589A | 1989-01-30 | 1989-01-30 | |
US302985 | 1989-01-30 | ||
US34689489A | 1989-05-03 | 1989-05-03 | |
US346894 | 1989-05-03 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0455719A1 EP0455719A1 (en) | 1991-11-13 |
EP0455719A4 true EP0455719A4 (en) | 1992-07-08 |
Family
ID=26973198
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19900902924 Withdrawn EP0455719A4 (en) | 1989-01-30 | 1990-01-25 | Composition and treatment with peptide combinations |
Country Status (5)
Country | Link |
---|---|
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)
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 |
AU2161592A (en) * | 1991-06-12 | 1993-01-12 | Magainin Pharmaceuticals, Inc. | 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 |
DE69637731D1 (en) | 1995-08-23 | 2008-12-11 | Univ British Columbia | Antimicrobial cationic peptides and methods for their identification |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1988006597A1 (en) * | 1987-03-04 | 1988-09-07 | The United States Of America, As Represented By Th | New synthetic bioactive compounds and method of producing bioactive effect |
-
1990
- 1990-01-17 CA CA002007913A patent/CA2007913A1/en not_active Abandoned
- 1990-01-25 WO PCT/US1990/000460 patent/WO1990008552A1/en not_active Application Discontinuation
- 1990-01-25 JP JP2503427A patent/JPH04506056A/en active Pending
- 1990-01-25 EP EP19900902924 patent/EP0455719A4/en not_active Withdrawn
- 1990-01-25 AU AU50428/90A patent/AU5042890A/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1988006597A1 (en) * | 1987-03-04 | 1988-09-07 | The United States Of America, As Represented By Th | New synthetic bioactive compounds and method of producing bioactive effect |
Non-Patent Citations (1)
Title |
---|
See also references of WO9008552A1 * |
Also Published As
Publication number | Publication date |
---|---|
EP0455719A1 (en) | 1991-11-13 |
AU5042890A (en) | 1990-08-24 |
WO1990008552A1 (en) | 1990-08-09 |
CA2007913A1 (en) | 1990-07-30 |
JPH04506056A (en) | 1992-10-22 |
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Legal Events
Date | Code | Title | Description |
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
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Effective date: 19910529 |
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Owner name: THE CHILDREN'S HOSPITAL OF PHILADELPHIA |
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17Q | First examination report despatched |
Effective date: 19940627 |
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STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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18D | Application deemed to be withdrawn |
Effective date: 19951201 |