Format

Send to

Choose Destination
Eur J Med Chem. 2017 Jan 27;126:502-516. doi: 10.1016/j.ejmech.2016.11.027. Epub 2016 Nov 14.

Structure-based exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design of potent and permeable inhibitors.

Author information

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.

KEYWORDS:

3CL protease; Norovirus; Optimization; S4 subsite

PMID:
27914364
PMCID:
PMC5501333
DOI:
10.1016/j.ejmech.2016.11.027
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center