Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 2. Peptide structure-activity studies

被引：85

作者：

Dragovich, PS ^{[1
]}

Webber, SE ^{[1
]}

Babine, RE ^{[1
]}

Fuhrman, SA ^{[1
]}

Patick, AK ^{[1
]}

Matthews, DA ^{[1
]}

Reich, SH ^{[1
]}

Marakovits, JT ^{[1
]}

Prins, TJ ^{[1
]}

Zhou, R ^{[1
]}

Tikhe, J ^{[1
]}

Littlefield, ES ^{[1
]}

Bleckman, TM ^{[1
]}

Wallace, MB ^{[1
]}

Little, TL ^{[1
]}

Ford, CE ^{[1
]}

Meador, JW ^{[1
]}

Ferre, RA ^{[1
]}

Brown, EL ^{[1
]}

Binford, SL ^{[1
]}

DeLisle, DM ^{[1
]}

Worland, ST ^{[1
]}

机构：

[1] Agouron Pharmaceut Inc, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 15期

关键词：

D O I：

10.1021/jm9800696

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The structure-based design, chemical synthesis, and biological evaluation of various peptide-derived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of an ethyl propenoate Michael acceptor moiety and a tripeptidyl binding determinant. The systematic modification of each amino acid residue present in the binding determinant as well as the N-terminal functionality is described. Such modifications are shown to provide irreversible HRV-14 3CP inhibitors with anti-3CP activities (k(obs)/[I]) ranging from 60 to 280 000 M-1 s(-1) and antiviral EC50's which approach 0.15 mu M. An optimized inhibitor which incorporates several improvements identified by the structure-activity studies is also described. This molecule displays very rapid irreversible inhibition of HRV-14 3CP (k(obs)/[I] = 800 000 M-1 s(-1)) and potent antiviral activity against HRV-14 in cell culture (EC50 = 0.056 mu M). A 1.9 Angstrom crystal structure of an S-alkylthiocarbamate-containing inhibitor complexed with HRV-8 3CP is also detailed.

引用

页码：2819 / 2834

页数：16

共 44 条

[1] BIOLOGICALLY-ACTIVE PROTEASE 3C OF HUMAN RHINOVIRUS 1A IS EXPRESSED FROM A CLONED CDNA SEGMENT IN ESCHERICHIA-COLI [J].