3ur9
1.65A resolution structure of Norwalk Virus Protease Containing a covalently bound dipeptidyl inhibitor
Structural highlights
FunctionPOLG_NVN68 Protein p48 may play a role in viral replication by interacting with host VAPA, a vesicle-associated membrane protein that plays a role in SNARE-mediated vesicle fusion. This interaction may target replication complex to intracellular membranes.[1] [2] NTPase presumably plays a role in replication. Despite having similarities with helicases, does not seem to display any helicase activity.[3] [4] Protein P22 may play a role in targeting replication complex to intracellular membranes.[5] [6] Viral genome-linked protein is covalently linked to the 5'-end of the positive-strand, negative-strand genomic RNAs and subgenomic RNA. Acts as a genome-linked replication primer. May recruit ribosome to viral RNA thereby promoting viral proteins translation.[7] [8] 3C-like protease processes the polyprotein: 3CLpro-RdRp is first released by autocleavage, then all other proteins are cleaved. May cleave host polyadenylate-binding protein thereby inhibiting cellular translation (By similarity).[9] [10] RNA-directed RNA polymerase replicates genomic and antigenomic RNA by recognizing replications specific signals. Transcribes also a subgenomic mRNA by initiating RNA synthesis internally on antigenomic RNA. This sgRNA encodes for structural proteins. Catalyzes the covalent attachment VPg with viral RNAs (By similarity).[11] [12] 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[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
