基于结构的不可逆人鼻病毒3C蛋白酶抑制剂的设计、合成及生物学评价。1. 迈克尔受体结构-活性研究。

Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 1. Michael acceptor structure-activity studies.

作者信息

Dragovich P S, Webber S E, Babine R E, Fuhrman S A, Patick A K, Matthews D A, Lee C A, Reich S H, Prins T J, Marakovits J T, Littlefield E S, Zhou R, Tikhe J, Ford C E, Wallace M B, Meador J W, Ferre R A, Brown E L, Binford S L, Harr J E, DeLisle D M, Worland S T

机构信息

Agouron Pharmaceuticals, Inc., 3565 General Atomics Court, San Diego, California 92121, USA.

出版信息

J Med Chem. 1998 Jul 16;41(15):2806-18. doi: 10.1021/jm980068d.

DOI:10.1021/jm980068d

PMID:9667970

Abstract

The structure-based design, chemical synthesis, and biological evaluation of peptide-derived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds incorporate various Michael acceptor moieties and are shown to irreversibly bind to HRV serotype 14 3CP with inhibition activities (kobs/[I]) ranging from 100 to 600 000 M-1 s-1. These inhibitors are also shown to exhibit antiviral activity when tested against HRV-14-infected H1-HeLa cells with EC50's approaching 0.50 microM. Extensive structure-activity relationships developed by Michael acceptor alteration are reported along with the evaluation of several compounds against HRV serotypes other than 14. A 2.0 A crystal structure of a peptide-derived inhibitor complexed with HRV-2 3CP is also detailed.

摘要

本文描述了基于结构的肽源人鼻病毒（HRV）3C蛋白酶（3CP）抑制剂的设计、化学合成及生物学评价。这些化合物含有各种迈克尔受体基团，显示出与HRV 14型3CP不可逆结合，抑制活性（kobs/[I]）范围为100至600000 M-1 s-1。当针对HRV-14感染的H1-HeLa细胞进行测试时，这些抑制剂还显示出抗病毒活性，其半数有效浓度（EC50）接近0.50 microM。报告了通过改变迈克尔受体建立的广泛构效关系，以及对几种针对14型以外HRV血清型的化合物的评价。还详细介绍了一种与HRV-2 3CP复合的肽源抑制剂的2.0 Å晶体结构。