Human noroviruses are the primary cause of acute viral gastroenteritis (“stomach flu”). Noroviruses are highly contagious and refractory to common disinfectants, consequently, they are associated with high morbidity among vulnerable populations and exact a heavy financial burden on public healthcare. Combating noroviruses presents a formidable challenge because of their high infectivity, genetic diversity, and environmental stability. Thus, there is an urgent need for the development of effective therapeutics and/or prophylactics for the management of norovirus infections. Noroviruses (NV) are positive sense icosahedral RNA viruses that belong to the Caliciviridae family. The norovirus life cycle entails the processing of the viral polyprotein into structural and nonstructural proteins by norovirus 3CL protease (3CLpro), 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 a 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. Norovirus 3CLpro is essential for viral replication, consequently, it’s an attractive target for the development of anti-norovirus therapeutics and prophylactics. We have recently reported structure-activity relationship studies, including X-ray crystallographic, cell-based, and in vivo biochemical studies, aimed at optimizing the potency of a series of norovirus 3CL protease dipeptidyl inhibitors and illuminating their mechanism of action. We report herein the structure-guided cap-centered optimization of potency and pharmacokinetics of the dipeptidyl series of norovirus 3CL protease inhibitors.

Structure-guided cap-centered optimization of potency and pharmacokinetics of norovirus 3CL protease inhibitors

251st National Meeting (2016)

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