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Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses
dc.contributor.author | Yunjeong, Kim | |
dc.contributor.author | Lovell, Scott | |
dc.contributor.author | Tiew, Kok-Chuan | |
dc.contributor.author | Mandadapu, Sivakoteswara Rao | |
dc.contributor.author | Alliston, Kevin R. | |
dc.contributor.author | Battaile, Kevin P. | |
dc.contributor.author | Groutas, William C. | |
dc.contributor.author | Chang, Kyeong-Ok | |
dc.date.accessioned | 2015-12-16T19:19:31Z | |
dc.date.available | 2015-12-16T19:19:31Z | |
dc.date.issued | 2012-08-22 | |
dc.identifier.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 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/19226 | |
dc.description | This is the published version. Copyright American Society for Microbiology | en_US |
dc.description.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. | en_US |
dc.publisher | American Society for Microbology | en_US |
dc.title | Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses | en_US |
dc.type | Article | |
kusw.kuauthor | Lovell, Scott W. | |
kusw.kudepartment | Higuchi Biosciences Center | en_US |
dc.identifier.doi | 10.1128/JVI.01348-12 | |
kusw.oaversion | Scholarly/refereed, publisher version | |
kusw.oapolicy | This item meets KU Open Access policy criteria. | |
dc.rights.accessrights | openAccess |