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

Click on the DOI link to access the article (may not be free).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.The generous financial support of this work by the National Institutes of Health (AI109039) is gratefully acknowledged. Use of the University of Kansas Protein Structure Laboratory was supported by grants from the National Center for Research Resources (5P20RR017708-10) and the National Institute of General Medical Sciences (8P20GM103420-10). Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman-Woodward Medical Research Institute. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-06CH11357