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
Kankanamalage, Anushka C. Galasiti
Weerawarna, Pathum M.
Uy, Roxanne Adeline Z.
Damalanka, Vishnu C.
Mandadapu, Sivakoteswara Rao
Alliston, Kevin R.
Battaile, Kevin P.
Groutas, William C.
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Anushka C. Galasiti Kankanamalage, Yunjeong Kim, Pathum M. Weerawarna, Roxanne Adeline Z. Uy, Vishnu C. Damalanka, Sivakoteswara Rao Mandadapu, Kevin R. Alliston, Nurjahan Mehzabeen, Kevin P. Battaile, Scott Lovell, Kyeong-Ok Chang, and William C. Groutas. 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 2015 58 (7), 3144-3155
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.
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