Cysteic acid derivatives of anti-viral peptides

A cysteic acid and virus technology, applied in the direction of viral peptides, antiviral agents, viruses, etc., can solve the problems of poor solubility and short cytoplasmic half-life in vivo

Inactive Publication Date: 2010-03-31
CONJUCHEM BIOTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although many antiviral or anti-fusogenic peptides described in the art exhibit potent antiviral and / or anti-fusogenic activity, these peptides suffer from poor solubility in aqueous formulations at physiological pH, and in vivo Disadvantages of short cytoplasmic half-life

Method used

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  • Cysteic acid derivatives of anti-viral peptides
  • Cysteic acid derivatives of anti-viral peptides
  • Cysteic acid derivatives of anti-viral peptides

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-5

[0306] Example 1-5: Synthesis and purification of C34 cysteine ​​sulfonic acid derivatives

[0307] Synthesis of cysteic acid derivatives of C34 was performed on a twelve-channel (Symphony) peptide synthesizer using an automated solid-phase method, with manual intervention during peptide generation. Synthesis was performed on Fmoc-protected Ramage amide linker resin using Fmoc-protected amino acids. The linkage uses O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) and diisopropylethylamine (DIEA) as an activator mixture in N , in N-dimethylformamide (DMF) solution. The Fmoc protecting group was removed using 20% ​​piperidine / DMF. Boc-protected amino acids are used at the N-terminus to generate free N when the peptide is cleaved from the resin α - end. Sigmacote-treated glass reaction vessels were used during the synthesis.

Embodiment 2

[0308] Embodiment 2: the synthesis of CA-C34

[0309] CA-C34 has the following amino acid sequence:

[0310] Cysteine-Trp-Met-Glu-Trp-Asp-Arg-Glu-Ile-Asn-Asn-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln -Asn-Gln-Gln-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-CONH 2 (SEQ ID NO: 2). CA-C34 modified peptides were synthesized as follows:

[0311] Step 1: Solid-phase peptide synthesis of CA-C34 was performed on a 100 μm scale using manual and automated solid-phase synthesis, twelve-channel (Symphony) peptide synthesizer and Ramage resin. Add the following protected amino acids to the resin sequentially: Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(tBu)-OH , Fmoc-Asn(Trt)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Asn( Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Ile-OH, Fmoc-Leu -OH, Fmoc-Ser(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu...

Embodiment 3

[0313] Embodiment 3: CA-C34 (Arg 28 )Synthesis

[0314] CA-C34 (Arg 28 ) has the following amino acid sequence:

[0315] Cysteine-Trp-Met-Glu-Trp-Asp-Arg-Glu-Ile-Asn-Asn-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln - Asn-Gln-Gln-Glu-Arg-Asn-Glu-Gln-Glu-Leu-Leu-CONH2 (SEQ ID NO: 3).

[0316] Step 1: CA-C34 (Arg 28 ) for solid-phase peptide synthesis. Add the following protected amino acids to the resin sequentially: Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(tBu)-OH , Fmoc-Asn(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Asn( Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Ile-OH, Fmoc-Leu -OH, Fmoc-Ser(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH , Fmoc-Tyr(tBu)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Ile-OH, Fmoc-Glu(tBu)-OH, Fmoc-Arg(Pbf)- OH, Fmoc-Asp(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Glu(tBu)-OH, Fmoc-M...

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Abstract

This invention relates to C34 peptide derivatives having improved aqueous solubility that are inhibitors of viral infection and / or exhibit antifusogenic properties. In particular, this invention relates to C34 derivatives having inhibiting activity against human immunodeficiency virus (HIV), respiratory synctial vims (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.

Description

[0001] Cross references to related applications [0002] This application claims priority to US Serial Nos. 60 / 938,380 and 60 / 938,394, filed May 16, 2007. The content of the above application is hereby incorporated by reference in its entirety. Background of the invention [0003] Human immunodeficiency virus type I (HIV-I) entry into uninfected cells involves three major steps: (i) gp120 binding to the CD4 receptor, (ii) subsequent binding to the co-receptors CXCR4 or CCR5, and (iii) HIV -I A series of conformational changes in the extracellular domain of the transmembrane glycoprotein gp41 that are important for initiating membrane fusion events that ultimately allow infection to occur. Viruses such as respiratory syncytial virus (RSV), human parainfluenza virus type 3 (HPIV-3), measles virus, and simian immunodeficiency virus (SIV) show high structural and functional similarities to HIV, including gp41-like proteins . [0004] Several small molecule drug candidates, inc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/16
CPCC12N2740/16122A61K38/00C07K14/005A61P31/14A61P31/18Y02A50/30
Inventor 奥马·库雷希马丁·罗比塔耶多米尼克·P·布赖顿
Owner CONJUCHEM BIOTECH INC
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