Structural basis of inhibition specificities of 3C and 3C-like proteases by zinc-coordinating and peptidomimetic compounds

Cheng Chung Lee, Chih Jung Kuo, Tzu Ping Ko, Min Feng Hsu, Yao Chen Tsui, Shih Cheng Chang, Syaulan Yang, Shu Jen Chen, Hua Chien Chen, Ming Chu Hsu, Shin Ru Shih, Po Huang Liang, Andrew H.J. Wang

Research output: Contribution to journalArticlepeer-review

83 Citations (Scopus)

Abstract

Human coxsackievirus (CV) belongs to the picornavirus family, which consists of over 200 medically relevant viruses. In picornavirus, a chymotrypsin-like protease (3Cpro) is required for viral replication by processing the polyproteins, and thus it is regarded as an antiviral drug target. A 3C-like protease (3CLpro) also exists in human coronaviruses (CoV) such as 229E and the one causing severe acute respiratory syndrome (SARS). To combat SARS, we previously had developed peptidomimetic and zinc-coordinating inhibitors of 3CLpro. As shown in the present study, some of these compounds were also found to be active against 3Cpro of CV strain B3 (CVB3). Several crystal structures of 3Cpro from CVB3 and 3CLpro from CoV-229E and SARS-CoV in complex with the inhibitors were solved. The zinc-coordinating inhibitor is tetrahedrally coordinated to the His40-Cys147 catalytic dyad of CVB3 3Cpro. The presence of specific binding pockets for the residues of peptidomimetic inhibitors explains the binding specificity. Our results provide a structural basis for inhibitor optimization and development of potential drugs for antiviral therapies.

Original languageEnglish
Pages (from-to)7646-7655
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number12
DOIs
Publication statusPublished - Mar 20 2009
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Structural basis of inhibition specificities of 3C and 3C-like proteases by zinc-coordinating and peptidomimetic compounds'. Together they form a unique fingerprint.

Cite this