Anushka C Galasiti Kankanamalage1, Yunjeong Kim2, Athri D Rathnayake1, Vishnu C Damalanka1, Pathum M Weerawarna1, Sean T Doyle1, Amer F Alsoudi1, D M Padmasankha Dissanayake1, Gerald H Lushington3, Nurjahan Mehzabeen4, Kevin P Battaile5, Scott Lovell4, Kyeong-Ok Chang6, William C Groutas7. 1. Department of Chemistry, Wichita State University, Wichita, KS 67260, USA. 2. Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA. 3. LiS Consulting, Lawrence, KS 66046, USA. 4. Protein Structure Laboratory, The University of Kansas, Lawrence, KS 66047, USA. 5. IMCA-CAT, Hauptman-Woodward Medical Research Institute, APS Argonne National Laboratory, Argonne, IL 60439, USA. 6. Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA. Electronic address: kchang@vet.ksu.edu. 7. Department of Chemistry, Wichita State University, Wichita, KS 67260, USA. Electronic address: bill.groutas@wichita.edu.
Abstract
Human noroviruses are the primary cause of epidemic and sporadic acute gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised patients and children, constitute a serious public health concern. There are currently no approved human vaccines or norovirus-specific small-molecule therapeutics or prophylactics. Norovirus 3CL protease has recently emerged as a potential therapeutic target for the development of anti-norovirus agents. We hypothesized that the S4 subsite of the enzyme may provide an effective means of designing potent and cell permeable inhibitors of the enzyme. We report herein the structure-guided exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design and synthesis of effective inhibitors of the protease. Published by Elsevier Masson SAS.
Human noroviruses are the primary cause of epidemic and sporadic acute pan class="Disease">gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised patients and children, constitute a serious public health concern. There are currently no approved human vaccines or norovirus-specific small-molecule therapeutics or prophylactics. Norovirus 3CL protease has recently emerged as a potential therapeutic target for the development of anti-norovirus agents. We hypothesized that the S4 subsite of the enzyme may provide an effective means of designing potent and cell permeable inhibitors of the enzyme. We report herein the structure-guided exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design and synthesis of effective inhibitors of the protease. Published by Elsevier Masson SAS.
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