Inhibition of hepatitis C virus NS3 protease by peptides derived from complementarity‐determining regions (CDRs) of the monoclonal antibody 8D4: tolerance of a CDR peptide to conformational changes of a target

FEBS Letters

Misawa, Satoru²  Ohba, Yoichi²  Watanabe, Hideki¹  Kumagai, Izumi¹  Asano, Ryutaro³  Kasai, Nobuhiro¹  Ueno, Takamasa²  Hayashi, Hideya²  Tsumoto, Kouhei¹ 

[1] Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Sendai 980-8579, Japan;Pharmaceuticals and Biotechnology Laboratory, Japan Energy Corporation, Toda city, Saitama 335-8502, Japan;Cell Resource Center for Biomedical Research, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryomachi, Aoba-ku, Sendai 980-8575, Japan

关键词: CDR peptide;    Antibody;    Conformational change;    Circularization;    NS3 protease;    Fv;    antibody variable domain fragment;    HCV;    hepatitis C virus;    NS;    non-structural protein;    K i;    inhibition constant;    CHAPS;    3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate;    CDR;    complementarity-determining region;    Abz;    fluorophore 2-aminobenzoyl;    TFA;    trifluoroacetic acid;    HPLC;    high-performance liquid chromatography;   

DOI  :  10.1016/S0014-5793(02)03090-9

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

We have synthesized and characterized peptides derived from complementarity-determining regions (CDRs) of 8D4, a mouse monoclonal antibody against NS3 protease domain of hepatitis C virus. 8D4 inhibits enzymatic activity without its cofactor, NS4A peptide. One of the synthetic peptides derived from CDRs, CDR1 of the heavy-chain (CDR-H1) peptide strongly inhibited NS3 protease activity competitively in the absence of NS4A and non-competitively in the presence of NS4A. Moreover, cyclic CDR-H1 peptides bridged by disulfide inhibited NS3 protease more potently. The chain length of the CDR-H1 peptide is critical for strong inhibition, even when the peptide is circularized. This finding suggests the importance of peptide conformation. In contrast to a cognate antibody molecule, CDR-derived peptides may provide good ligands for target molecules by having a tolerance to conformational changes of the targets caused by cofactor binding or mutation.

【 授权许可】

Unknown