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.

Galasiti Kankanamalage, Anushka C; Kim, Yunjeong; Weerawarna, Pathum M; Uy, Roxanne Adeline Z; Damalanka, Vishnu C; Mandadapu, Sivakoteswara Rao; Alliston, Kevin R; Mehzabeen, Nurjahan; Battaile, Kevin P; Lovell, Scott; Chang, Kyeong-Ok; Groutas, William C

Norovirus 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 antinorovirus 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.