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Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses
| Content Provider | Semantic Scholar |
|---|---|
| Author | Kim, Yunjeong Lovell, Scott Tiew, Kok-Chuan Mandadapu, Sivakoteswara Rao Alliston, Kevin R. Battaile, Kevin P. Groutas, William C. Chang, Kyeong-Ok |
| Copyright Year | 2012 |
| 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. |
| File Format | PDF HTM / HTML |
| DOI | 10.1128/jvi.01348-12 |
| Journal | Journal of Virology |
| PubMed Central reference number | PMC3486288 |
| PubMed reference number | 22915796 |
| Language | English |
| Publisher | PMC |
| Access Restriction | Open |
| Rights Holder | unk |
| Content Type | Text |
| Resource Type | Article Preprint |
