Journal
CHEMICAL BIOLOGY & DRUG DESIGN
Volume 72, Issue 1, Pages 34-49Publisher
WILEY
DOI: 10.1111/j.1747-0285.2008.00679.x
Keywords
biophysical chemistry; calorimetric techniques; drug design; drug discovery; protease and ligands (substrate/inhibitor)
Funding
- NIGMS NIH HHS [R01 GM057144, GM 57144, R01 GM057144-11] Funding Source: Medline
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Coronaviruses comprise a large group of RNA viruses with diverse host specificity. The emergence of highly pathogenic strains like the SARS coronavirus (SARS-CoV), and the discovery of two new coronaviruses, NL-63 and HKU1, corroborates the high rate of mutation and recombination that have enabled them to cross species barriers and infect novel hosts. For that reason, the development of broad-spectrum antivirals that are effective against several members of this family is highly desirable. This goal can be accomplished by designing inhibitors against a target, such as the main protease 3CL(pro) (M-pro), which is highly conserved among all coronaviruses. Here 3CL(pro) derived from the SARS-CoV was used as the primary target to identify a new class of inhibitors containing a halomethyl ketone warhead. The compounds are highly potent against SARS 3CL(pro) with K-i's as low as 300 nM. The crystal structure of the complex of one of the compounds with 3CL(pro) indicates that this inhibitor forms a thioether linkage between the halomethyl carbon of the warhead and the catalytic Cys 145. Furthermore, Structure Activity Relationship (SAR) studies of these compounds have led to the identification of a pharmacophore that accurately defines the essential molecular features required for the high affinity.
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