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Antipathogenic synthetic piptides and compositions comprising them

A technology of pathogens and mixtures, which can be used in antiviral agents, drug combinations, medical preparations containing active ingredients, etc., and can solve problems such as lack of antibacterial activity

Inactive Publication Date: 2000-05-10
YEDA RES & DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Analogues with L to D substitutions of magainin were also found to lack antibacterial activity (Chen et al., 1988)

Method used

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  • Antipathogenic synthetic piptides and compositions comprising them
  • Antipathogenic synthetic piptides and compositions comprising them
  • Antipathogenic synthetic piptides and compositions comprising them

Examples

Experimental program
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Effect test

preparation example Construction

[0106] (v) Preparation of lipid vesicles

[0107] Small unilamellar vesicles (SUV) were prepared by sonication of PC / cholesterol (10:1, w / w) or PC / PS (1:1, w / w) dispersions. Briefly, dry lipid and cholesterol (10:1, w / w) were dissolved in CHCl 3 / MeOH mixture (2:1, V / V). The solvent was then evaporated in a nitrogen stream, and the lipid (concentration: 7.2 mg / ml) was treated in vacuo for 1 hour, then re-dissolved in a suitable buffer with vigorous shaking. The obtained lipid dispersion was sonicated for 5-15 minutes in a tank-type ultrasonic instrument (G1125SP1 ultrasonic instrument, Laboratory Supplies Company Inc. NY) until clear. Lipid concentrations in the resulting preparations were determined by phosphorus analysis (Bartlett, 1959). Vesicles were observed with a JEOL JEM 100B electron microscope (Japen Electron Optics Laboratory Co., Tokyo, Japan) as follows. A drop of vesicles was placed on a carbon-coated grid and negatively stained with uranyl acetate. Examinat...

Embodiment 1

[0127] Example 1 Synthesis and biological activity of diastereomers derived from pardaxin

[0128] 1.1 Synthesis

[0129] To examine the role of the α-helical structure of polycationic cytolysins in their cytotoxicity against mammalian cells and bacteria, we synthesized a series of pardaxins as described in Experimental Methods (ii) and (iii) The derived peptides were analyzed for their structure, hemolytic activity on hRBC, antibacterial activity and effect on bacterial morphology.

[0130] pardaxin (par) is a 33-mer peptide with the following sequence

[0131] Gly-Phe-Phe-Ala-Leu-Ile-Pro-Lys-Ile-Ile-Ser-

[0132] Ser-Pro-Leu-Phe-Lys-Thr-Leu-Leu-Ser-Ala-Val-

[0133] Gly-Ser-Ala-Leu-Ser-Ser-Ser-Gly-Gly-Gln-Glu

[0134] To introduce a positive charge, the modification of the pardaxin molecule is carried out by deleting the acidic C-terminus of pardaxin, or converting the acidic C-terminus of pardaxin or its fragments to be positively charged by placing the carboxyl group o...

Embodiment 2

[0177] Example 2 Synthesis and biological activity of diastereomers derived from melittin

[0178] 2.1 Synthesis

[0179] In order to further examine the role of the α-helical structure of cytolysin in its cytotoxicity to mammalian cells and bacteria, and to understand the inner mechanism of this action, we synthesized four diastereomers of melittin (mel).

[0180] melittin is a 26-mer peptide with the following sequence Gly-Ile-Gly-Ala-Val-Leu-Lys-Val-Leu-Thr-Thr-Gly-Leu-Pro-Ala-Leu-Ile-Ser-Trp-Ile -Lys-Arg-Lys-Arg-Gln-Gln-NH 2

[0181] To introduce a positive charge, melittin is modified by converting the acidic C-terminus of melittin or fragments thereof to be positively charged by reacting the C-terminal carboxyl group with ethylenediamine. In melittin diastereomers, the N-helix and C-helix are replaced by D-Val, D-Ile and D-Lys, respectively, of the two Val residues at positions 5 and 8 of melittin, the Ile residue at position 17, Lys residue at position 21 to change ...

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Abstract

Non-hemolytic cytolytic agents selected from peptides, complexes of bundled peptides, mixtures of peptides or random peptide copolymers have a selective cytolytic activity manifested in that they have a cytolytic activity on pathogenic cells, being cells which are non-naturally occurring within the body consisting of microbial pathogenic organisms and malignant cells; and are non-hemolytic, having no cytolytic effect on red blood cells. The peptides may be cyclic derivatives of natural peptides such as pardaxin and mellitin and fragments thereof in which L-amino acid residues are replaced by corresponding D-amino acid residues, or are diastereomers of linear peptides composed of varying ratios of at least one positively charged amino acid and at least one hydrophobic amino acid, and in which at least one of the amino acid residues is a D-amino acid. Pharmaceutical compositions comprising the non-hemolytic cytolytic agents can be used for the treatment of several diseases caused by pathogens including antibacterial, fungal, viral, mycoplasma and protozoan infections and for the treatment of cancer.

Description

field of invention [0001] The present invention relates to novel non-hemolytic cytolytic polypeptides, compositions containing the polypeptides, and their use in the treatment of diseases or disorders and in agriculture. Background of the invention [0002] In the following, references are made to the prior art documents, and a full listing of references can be found in the "References" section at the end of the specification preceding the claims. [0003] The increasing resistance of microorganisms to available antimicrobial drugs has prompted extensive research to develop alternative antimicrobial compounds. [0004] In addition to, or in addition to, highly specific cell-mediated immune responses, vertebrates and other organisms possess defense systems consisting of diverse families of broad-spectrum cytolytic, eg antimicrobial, peptides. [0005] Lipid-peptide interaction studies of such cytolytic peptides, also known as cytolysins, tend to emphasize t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61KA61P31/04A61P31/10A61P31/12A61P33/02A61K38/00C07K7/52C07K14/00C07K14/435C07K14/46C07K14/47
CPCC07K14/001A61K38/00C07K14/43572C07K14/461A61P31/04A61P31/10A61P31/12A61P33/02
Inventor Y·沙依Z·奥伦
Owner YEDA RES & DEV CO LTD
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