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.
- 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.
- 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 Laboratory (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
- 36 MATERIALS SCIENCE