Stable Benzotriazole Esters as Mechanism-Based Inactivators of the Severe Acute Respiratory Syndrome 3CL Protease

Chung Yi Wu, Ke Yung King, Chih Jung Kuo, Jim Min Fang, Ying Ta Wu, Ming Yi Ho, Chung Lin Liao, Jiun Jie Shie, Po Huang Liang, Chi Huey Wong

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

Severe acute respiratory syndrome (SARS) is caused by a newly emerged coronavirus that infected more than 8000 individuals and resulted in more than 800 fatalities in 2003. Currently, there is no effective treatment for this epidemic. SARS-3CLpro has been shown to be essential for replication and is thus a target for drug discovery. Here, a class of stable benzotriazole esters was reported as mechanism-based inactivators of 3CLpro, and the most potent inactivator exhibited a kinact of 0.0011 s-1 and a Ki of 7.5 nM. Mechanistic investigation with kinetic and mass spectrometry analyses indicates that the active site Cys145 is acylated, and that no irreversible inactivation was observed with the use of the C145A mutant. In addition, a noncovalent, competitive inhibition became apparent by using benzotriazole ester surrogates in which the bridged ester-oxygen group is replaced with carbon. © 2006 Elsevier Ltd. All rights reserved.
Original languageEnglish
JournalChemistry and Biology
Volume13
Issue number3
DOIs
StatePublished - 1 Mar 2006

Fingerprint Dive into the research topics of 'Stable Benzotriazole Esters as Mechanism-Based Inactivators of the Severe Acute Respiratory Syndrome 3CL Protease'. Together they form a unique fingerprint.

Cite this