Kankanamalage, Anushka C. GalasitiKim, YunjeongWeerawarna, Pathum M.Uz, Roxanne Adeline Z.Damalanka, Vishnu C.Mandadapu, Sivakoteswara RaoAlliston, Kevin R.Mehzabeen, NurjahanBattaile, Kevin P.Lovell, ScottChang, Kyeong-OkGroutas, William C.2017-04-122017-04-122015-04-09Kankanamalage, A. C. G., Kim, Y., Weerawarna, P. M., Uy, R. A. Z., Damalanka, V. C., Mandadapu, S. R., … Groutas, W. C. (2015). Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure-Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies. Journal of Medicinal Chemistry, 58(7), 3144–3155. http://doi.org/10.1021/jm5019934https://hdl.handle.net/1808/23628Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of anti-norovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm5019934.Article10.1021/jm5019934openAccess