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Eur J Med Chem. 2018 Apr 25;150:334-346. doi: 10.1016/j.ejmech.2018.03.004. Epub 2018 Mar 6.

Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element.

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
Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, 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
LiS Consulting, Lawrence, KS 66046, USA.
7
Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA. Electronic address: kchang@vet.ksu.edu.
8
Department of Chemistry, Wichita State University, Wichita, KS 67260, USA. Electronic address: bill.groutas@wichita.edu.

Abstract

There are currently no approved vaccines or small molecule therapeutics available for the prophylaxis or treatment of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections. MERS-CoV 3CL protease is essential for viral replication; consequently, it is an attractive target that provides a potentially effective means of developing small molecule therapeutics for combatting MERS-CoV. We describe herein the structure-guided design and evaluation of a novel class of inhibitors of MERS-CoV 3CL protease that embody a piperidine moiety as a design element that is well-suited to exploiting favorable subsite binding interactions to attain optimal pharmacological activity and PK properties. The mechanism of action of the compounds and the structural determinants associated with binding were illuminated using X-ray crystallography.

KEYWORDS:

3CL protease; Antiviral; MERS-CoV; Peptidomimetic inhibitors; Piperidine moiety

PMID:
29544147
PMCID:
PMC5891363
DOI:
10.1016/j.ejmech.2018.03.004
[Indexed for MEDLINE]
Free PMC Article

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