In vitro evolution of an HIV integrase binding protein from a library of C-terminal domain γS-crystallin variants

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Moody, Issa S.²  Verde, Shawn C.¹  Overstreet, Cathie M.²  Robinson, W. Edward, Jr.¹  Weiss, Gregory A.^2,3 

[1] Univ Calif Irvine, Dept Pathol & Lab Med, Irvine, CA 92697 USA

[2] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA

[3] Univ Calif Irvine, Dept Chem, Irvine, CA 92697 USA

关键词: HIV integrase;    Phage display;    Binding proteins;    Enzyme inhibitors;    Drug resistance;   

DOI  :  10.1016/j.bmcl.2012.07.008

来源: Elsevier

【 摘 要 】

A protein without natural binding functions was engineered to bind HIV-1 integrase. Phage display selections applied a library of variants based on the C-terminal domain of the eye lens protein human gamma S-crystallin. Multiple loop regions were altered to encode libraries with approximate to 3.6 x 10(11) different variants. A crystallin variant, termed integrase binding protein-10 (IBP-10), inhibits integrase catalysis with nano-molar K-i values. IBP-10 interacts with the integrase C-terminal domain and inhibits integrase substrate affinity. This allosteric mechanism allows IBP-10 to inhibit drug-resistant integrase variants. The results demonstrate the applicability of the crystallin scaffold for the discovery of binding partners and enzyme inhibitors. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

Free