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    Broad-spectrum antivirals against 3C or 3C-like proteases of picornaviruses, noroviruses, and coronaviruses

    Date
    2012-08-22
    Author
    Kim, Yunjeong
    Lovell, Scott
    Tiew, Kok-Chuan
    Mandadapu, Sivakoteswara Rao
    Alliston, Kevin R.
    Battaile, Kevin P.
    Groutas, William C.
    Chang, Kyeong-Ok
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    Citation
    Kim, Yunjeong; Lovell, Scott; Tiew, Kok-Chuan; Mandadapu, Sivakoteswara Rao; Alliston, Kevin R.; Battaile, Kevin P.; Groutas, William C.; Chang, Kyeong-Ok. 2012. Broad-spectrum antivirals against 3C or 3C-like proteases of picornaviruses, noroviruses, and coronaviruses. Journal of Virology, v.86 no.21 pp.11754-11762
    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
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    URI
    http://dx.doi.org/10.1128/JVI.01348-12
    http://hdl.handle.net/10057/5905
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