Loading...
Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses
Yunjeong, Kim Lovell, Scott Tiew, Kok-Chuan Mandadapu, Sivakoteswara Rao Alliston, Kevin R. Battaile, Kevin P. Groutas, William C. Chang, Kyeong-Ok
Yunjeong, Kim
Lovell, Scott
Tiew, Kok-Chuan
Mandadapu, Sivakoteswara Rao
Alliston, Kevin R.
Battaile, Kevin P.
Groutas, William C.
Chang, Kyeong-Ok
Citations
Altmetric:
Abstract
Phylogenetic analysis has demonstrated that some positive-sense RNA viruses can be classified into the picornavirus-like supercluster, which includes picornaviruses, caliciviruses, and coronaviruses. These viruses possess 3C or 3C-like proteases (3Cpro or 3CLpro, respectively), which contain a typical chymotrypsin-like fold and a catalytic triad (or dyad) with a Cys residue as a nucleophile. The conserved key sites of 3Cpro or 3CLpro may serve as attractive targets for the design of broad-spectrum antivirals for multiple viruses in the supercluster. We previously reported the structure-based design and synthesis of potent protease inhibitors of Norwalk virus (NV), a member of the Caliciviridae family. We report herein the broad-spectrum antiviral activities of three compounds possessing a common dipeptidyl residue with different warheads, i.e., an aldehyde (GC373), a bisulfite adduct (GC376), and an α-ketoamide (GC375), against viruses that belong to the supercluster. All compounds were highly effective against the majority of tested viruses, with half-maximal inhibitory concentrations in the high nanomolar or low micromolar range in enzyme- and/or cell-based assays and with high therapeutic indices. We also report the high-resolution X-ray cocrystal structures of NV 3CLpro-, poliovirus 3Cpro-, and transmissible gastroenteritis virus 3CLpro- GC376 inhibitor complexes, which show the compound covalently bound to a nucleophilic Cys residue in the catalytic site of the corresponding protease. We conclude that these compounds have the potential to be developed as antiviral therapeutics aimed at a single virus or multiple viruses in the picornavirus-like supercluster by targeting 3Cpro or 3CLpro.
Description
This is the published version. Copyright American Society for Microbiology
Date
2012-08-22
Journal Title
Journal ISSN
Volume Title
Publisher
American Society for Microbology
Collections
Archive Status
This item contains archived web content.
Files
Loading...
lovell_antivirals.pdf
Adobe PDF, 1.27 MB
Research Projects
Organizational Units
Journal Issue
Keywords
Citation
Kim, Y., S. Lovell, K.-C. Tiew, S. R. Mandadapu, K. R. Alliston, K. P. Battaile, W. C. Groutas, and K.-O. Chang. "Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses." Journal of Virology 86.21 (2012): 11754-1762. http://dx. doi.org/10.1128/JVI.01348-12