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Long lasting fusion peptide inhibitors of viral infection

a technology of fusion peptides and inhibitors, which is applied in the field of modified peptides, can solve the problems of short plasma half-life of peptides and reduce the effective antiviral activity of peptides, and achieve the effects of increasing stability in vivo, and reducing susceptibility to peptidase or protease degradation

Inactive Publication Date: 2008-08-21
CONJUCHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention is about modified peptides that have anti-viral and anti-fusogenic activity. These modifications increase the stability of the peptides in the body and reduce their susceptibility to degradation by peptidases or proteases. This reduces the need for frequent administration of the peptides. The modified peptides can be used as a prophylactic or treatment for infection with various viruses, including HIV, RSV, HPV, measles virus, and SIV. The modifications involve the addition of a reactive group that can react with available functional groups on blood components to form stable bonds. The invention also includes compositions containing these modified peptides for the prevention and treatment of viral infections, including AIDS, RSV, HPV, measles virus, and SIV."

Problems solved by technology

While many of the anti-viral or anti-fusogenic peptides described in the art exhibit potent anti-viral and / or anti-fusogenic activity, these peptides suffer from short plasma half-lifes in vivo, primarily due to rapid serum clearance and peptidase and protease activity.
This in turn greatly reduces the effective anti-viral activity of the peptides.

Method used

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  • Long lasting fusion peptide inhibitors of viral infection
  • Long lasting fusion peptide inhibitors of viral infection
  • Long lasting fusion peptide inhibitors of viral infection

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of a Modified DP178—Synthesis of YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWFK(MPA)-NH2

[0167]In this example, DP178 (SEQ ID NO:1) is synthesized and modified to include a linker and maleimide group according to the following synthesis scheme. As reported in U.S. Pat. Nos. 6,013,236 and 6,020,459, DP178 is a potent inhibitor of HIV-1, and inhibits both cell-induced syncytia formation between HIV-1 infected and uninfected cells and infection of uninfected cells be cell-free HIV-1 virus.

[0168]Solid phase peptide synthesis of the modified peptide on a 100 μmole scale is performed using manual solid-phase synthesis, a Symphony Peptide Synthesizer and Fmoc protected Rink Amide MBHA. The following protected amino acids are sequentially added to resin: Fmoc-Lys(Aloc)-OH, Fmoc-Phe-OH, Fmoc-Trp(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Trp(Boc)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Leu-OH, Fmoc-Glu(tBu)-OH, Fmoc-Leu-OH, Fmoc-Leu-...

example 2

Preparation of a Modified DP107—Synthesis of

[0169]

NNLLRAIEAQQHLLQLTVWQIKQLQARILAVERYLKDQK(MPA)NH2

[0170]In this example, DP107 (SEQ ID NO:2) is synthesized and modified to include a linker and maleimide group according to the following synthesis scheme. As reported in U.S. Pat. Nos. 6,013,236 and 6,020,459, DP107 exhibits potent antiviral activity against HIV.

[0171]Solid phase peptide synthesis of the modified peptide on a 100 μmole scale is performed using manual solid-phase synthesis, a Symphony Peptide Synthesizer and Fmoc protected Rink Amide MBHA. The following protected amino acids are sequentially added to resin: Fmoc-Lys(Aloc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Val-OH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc-Ile-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Ala-OH, Fmoc-Gln(Trt)-OH, Fmoc-Leu-OH, Fmoc-Gln(Trt)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ile-OH, Fmoc-Gln(Trt)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Val-OH, Fmoc-Thr(tBu)-OH, ...

example 3

[0172]Preparation of a Modified anti-RSV Peptide (C Terminal)

[0173]In this example, the peptide VITIELSNIKENKCNGAKVKLIKQELDKYKNAV (SEQ ID NO:16) is modified to include a linker and maleimide group according to the synthesis scheme set forth below. As reported in U.S. Pat. Nos. 6,013,236 and 6,020,459, the native sequence (SEQ ID NO.) inhibits viral infection of respiratory syncytial virus (RSV), including inhibiting fusion and syncytia formation between RSV-infected and uninfected Hep-2 cells.

[0174]Solid phase peptide synthesis of the modified peptide on a 100 μmole scale is performed using manual solid-phase synthesis, a Symphony Peptide Synthesizer and Fmoc protected Rink Amide MBHA. The following protected amino acids are sequentially added to resin: Fmoc-Lys(Aloc)-OH, Fmoc-Val-OH, Fmoc-Ala-OH, Fmoc-Asn(Trt)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Leu-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-...

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Abstract

Peptides exhibiting anti-viral and anti-fusogenic activity are modified to provide greater stability and improved half-life in vivo. The selected peptides include fusion inhibitors DP178 and DP107 and related peptides and analogs thereof. The modified peptides are capable of forming covalent bonds with one or more blood components, preferably a mobile blood component.

Description

FIELD OF THE INVENTION[0001]This invention relates to modified peptides that are inhibitors of viral activity and / or exhibit antifusogenic properties. In particular, this invention relates to modified peptide inhibitors of human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), human parainfluenza virus (HPV), measles virus (MeV), and simian immunodeficiency virus (SIV) with long duration of action for the treatment of the respective viral infections. The invention also relates to conjugates of the modified peptides and endogenous carriers, particularly conjugates of the modified peptides and various mobile blood components, particularly mobile endogenous proteins.BACKGROUND OF THE INVENTION[0002]Membrane fusion events, while commonplace in normal cell biological processes, are also involved in a variety of disease states, including, for example the entry of enveloped viruses into cells. Peptides are known that inhibit or otherwise disrupt membrane fusion-associated e...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00C07K14/00C07K16/00A61K38/00A61P31/12A61P31/16A61P31/18C07K14/155C07K14/16
CPCA61K38/00C12N2740/16122C07K14/005A61P31/12A61P31/16A61P31/18A61P37/00
Inventor BRIDON, DOMINIQUE P.DUFRESNE, ROBERT S.BOUDJELLAB, NISSABROBITAILLE, MARTINMILNER, PETER G.
Owner CONJUCHEM
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