4f49
2.25A resolution structure of Transmissible Gastroenteritis Virus Protease containing a covalently bound Dipeptidyl Inhibitor2.25A resolution structure of Transmissible Gastroenteritis Virus Protease containing a covalently bound Dipeptidyl Inhibitor
Structural highlights
FunctionR1A_CVPPU The papain-like proteinase 1 (PLP1) and papain-like proteinase 2 (PLP2) are responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PLP2 possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. PLP2 also antagonizes innate immune induction of type I interferon by blocking the nuclear translocation of host IRF-3 (By similarity). The main proteinase 3CL-PRO is responsible for the majority of cleavages as it cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SAGC]. Inhibited by the substrate-analog Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK. Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter (By similarity). Nsp9 is a ssRNA-binding protein (By similarity). Publication Abstract from PubMedPhylogenetic 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 an attractive target for the design of broad-spectrum antivirals for multiple viruses in the supercluster. We have 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, aldehyde (GC373), bisulfite adduct (GC376) and alpha-ketoamide (GC375), against viruses that belong to the supercluster. All compounds were highly effective against the majority of tested viruses with the half maximal inhibitory concentration in the high nanomolar or low micromolar range in the enzyme and/or cell-based assays with high therapeutic indices. We also report the high-resolution X-ray cocrystal structures of the NV 3CLpro-, poliovirus 3Cpro- or transmissible gastroenteritis virus 3CLpro-inhibitor GC376 complex that 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. Broad-Spectrum Antivirals against 3C or 3C-like Proteases of Picornaviruses, Noroviruses and Coronaviruses.,Kim Y, Lovell S, Tiew KC, Mandadapu SR, Alliston KR, Battaile KP, Groutas WC, Chang KO J Virol. 2012 Aug 22. PMID:22915796[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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