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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

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.
 [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [3] ;  [4] ;  [3] ;  [2] ;  [1]
  1. Wichita State Univ., Wichita, KS (United States). Dept. of Chemistry
  2. Kansas State Univ., Manhattan, KS (United States). Dept. of Diagnostic Medicine & Pathobiology
  3. Univ. of Kansas, Lawrence, KS (United States). Protein Structure Lab.
  4. Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS). Hauptman-Woodward Medical Research Inst.
Publication Date:
OSTI Identifier:
Grant/Contract Number:
AC02-06CH11357; AI109039; 5P20RR017708-10; 8P20GM103420-10
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 58; Journal Issue: 7; Journal ID: ISSN 0022-2623
American Chemical Society (ACS)
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States