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 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
Kankanamalage, Anushka C. Galasiti
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
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2015-04-09
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Article
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Keywords
Rational drug design,Potent inhibition,Norwalk virus,Data quality,Macromolecular crystallography,Bisulfite adducts,Derivatives,Scaffold,Gastroenteritis,Inactivation
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Citation
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
Abstract
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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American Chemical Society
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Journal of Medicinal Chemistry;v.58:no.7
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0022-2623