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dc.contributor.authorKankanamalage, Anushka C. Galasiti
dc.contributor.authorWeerawarna, Pathum M.
dc.contributor.authorUy, Roxanne Adeline Z.
dc.contributor.authorMandadapu, Sivakoteswara Rao
dc.contributor.authorAlliston, Kevin R.
dc.contributor.authorChang, Kyeong-Ok
dc.contributor.authorKim, Yunjeong
dc.contributor.authorLovell, Scott
dc.contributor.authorHua, Duy H.
dc.contributor.authorPrior, Allan M.
dc.contributor.authorGroutas, William C.
dc.identifier.citationKankanamalage, Anushka C. Galasiti; Weerawarna, Pathum M.; Uy, Roxanne Adeline Z.; Mandadapu, Sivakoteswara Rao; Alliston, Kevin R.; Chang, Kyeong-Ok; Kim, Yunjeong; Lovell, Scott; Hua, Duy H.; Prior, Allan M.; Groutas, Willam C. 2014. Structure-based design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Abstracts of Papers of the American Chemical Society, Volume: 248 Meeting Abstract: 388-MEDIen_US
dc.descriptionPresented at the 248th National Meeting of the American Chemical Society (ACS), San Francisco, California on August 11, 2014.en_US
dc.description.abstractHuman noroviruses are the primary cause of sporadic and epidemic acute gastroenteritis in the US and worldwide. Noroviruses constitute an important public health problem, as well as a potential bioterrorism threat. The problem is further compounded by the current dearth of effective vaccines and norovirus-specific antiviral therapeutics and/or prophylactics. Human noroviruses are single-stranded, positive sense RNA viruses in the Caliciviridae family. Their ~7.5 kb genome encodes a polyprotein precursor that is processed by a virus-encoded 3CL protease (3CLpro) to generate mature non-structural proteins. Processing of the polyprotein is essential for virus replication, consequently NV 3CLpro has emerged as a potential druggable target for the discovery of anti-norovirus small molecule therapeutics and prophylactics. NV 3CLpro is a chymotrypsin-like cysteine protease with a Cys-His-Glu catalytic triad and an extended binding site. The primary substrate specificity of the protease is for P1 glutamine residue and a strong preference for a –D/E-F-X-L-Q-G-P- sequence, where X is H, Q or V, corresponding to the subsites S5-S4-S3-S2-S1-S1'-S2'-. Cleavage is at the P1-P1' (Q-G) scissile bond. We have recently reported the first high throughput FRET assay of 3CLpro from GI and GII noroviruses as a screening tool for identifying potential protease inhibitors and have determined the first high resolution X-ray crystal structures of NV 3CLpro in complex with peptidyl transition state inhibitors of the protease, as well as the first solution structure of the protease using high-field NMR. We report herein the structure-based optimization of a series of dipeptidyl inhibitors of NV 3CLpro using X-ray crystallography and an array of structure-activity relationship, biochemical, and cell-based studies.en_US
dc.publisherAmerican Chemical Societyen_US
dc.relation.ispartofseriesAbstracts of Papers of the American Chemical Society;248
dc.titleStructure-based design and optimization of dipeptidyl inhibitors of norovirus 3CL proteaseen_US
dc.rights.holderCopyright © 2015 American Chemical Society

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