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Eur J Med Chem. 2017 Feb 15;127:41-61. doi: 10.1016/j.ejmech.2016.12.033. Epub 2016 Dec 21.

Design, synthesis, and evaluation of a novel series of macrocyclic inhibitors of norovirus 3CL protease.

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

Norovirus infections have a major impact on public health worldwide, yet there is a current dearth of norovirus-specific therapeutics and prophylactics. This report describes the discovery of a novel class of macrocyclic inhibitors of norovirus 3C-like protease, a cysteine protease that is essential for virus replication. SAR, structural, and biochemical studies were carried out to ascertain the effect of structure on pharmacological activity and permeability. Insights gained from these studies have laid a solid foundation for capitalizing on the therapeutic potential of the series of inhibitors described herein.

KEYWORDS:

3CLprotease; Macrocyclic inhibitors; Norovirus

PMID:
28038326
PMCID:
PMC5296247
DOI:
10.1016/j.ejmech.2016.12.033
[Indexed for MEDLINE]
Free PMC Article

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