期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 150, 期 -, 页码 334-346出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.03.004
关键词
MERS-CoV; 3CL protease; Piperidine moiety; Antiviral; Peptidomimetic inhibitors
资金
- National Institute of General Medical Sciences of the National Institutes of Health [P30GM110761]
- Hauptman-Woodward Medical Research Institute
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- National Institutes of Health [R01 AI109039, P01 AI060699, R01 AI129269]
- faculty development KU Endowment Dolph Simons Award in Biomedical Sciences
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. (C) 2018 Elsevier Masson SAS. All rights reserved.
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