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.

doi:10.1021/jm5019934

Title: 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 Article · Wed Apr 08 20:00:00 EDT 2015 · Journal of Medicinal Chemistry

DOI: https://doi.org/10.1021/jm5019934 · OSTI ID:1179476

Galasiti Kankanamalage, Anushka C. ^[1]; Kim, Yunjeong ^[2]; Weerawarna, Pathum M. ^[1]; Uy, Roxanne Adeline Z. ^[1]; Damalanka, Vishnu C. ^[1]; Mandadapu, Sivakoteswara Rao ^[1]; Alliston, Kevin R. ^[1]; Mehzabeen, Nurjahan ^[3]; Battaile, Kevin P. ^[4]; Lovell, Scott ^[3]; Chang, Kyeong-Ok ^[2]; Groutas, William C. ^[1]

Wichita State Univ., Wichita, KS (United States). Dept. of Chemistry
Kansas State Univ., Manhattan, KS (United States). Dept. of Diagnostic Medicine & Pathobiology
Univ. of Kansas, Lawrence, KS (United States). Protein Structure Lab.
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS). Hauptman-Woodward Medical Research Inst.

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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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1179476

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 7 Vol. 58; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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