Journal article
Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element
European Journal of Medicinal Chemistry, Vol.150, pp.334-346
04/25/2018
DOI: 10.1016/j.ejmech.2018.03.004
PMCID: PMC5891363
PMID: 29544147
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. [Display omitted] •The structure-guided design of a new class of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) 3CL protease inhibitors was performed.•A piperidine moiety was used as a design element in the synthesis of peptidomimetic inhibitors that exploit interactions with the enzyme S3-S4 subsites.•The inhibitor design rationale was validated by X-ray crystallographic studies.•X-ray crystallography confirmed the mechanism of action of the inhibitors.
Details
- Title: Subtitle
- Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element
- Creators
- Anushka C Galasiti Kankanamalage - Wichita State UniversityYunjeong Kim - Kansas State UniversityVishnu C Damalanka - Wichita State UniversityAthri D Rathnayake - Wichita State UniversityAnthony R Fehr - University of IowaNurjahan Mehzabeen - University of KansasKevin P Battaile - Argonne National LaboratoryScott Lovell - University of KansasGerald H Lushington - LiS Consulting, Lawrence, KS 66046, USAStanley Perlman - University of Iowa, Microbiology and ImmunologyKyeong-Ok Chang - Kansas State UniversityWilliam C Groutas - Wichita State University
- Resource Type
- Journal article
- Publication Details
- European Journal of Medicinal Chemistry, Vol.150, pp.334-346
- DOI
- 10.1016/j.ejmech.2018.03.004
- PMID
- 29544147
- PMCID
- PMC5891363
- NLM abbreviation
- Eur J Med Chem
- ISSN
- 0223-5234
- eISSN
- 1768-3254
- Publisher
- Elsevier Masson SAS
- Grant note
- DOI: 10.13039/100000057, name: National Institute of General Medical Sciences, award: P30GM110761; DOI: 10.13039/100000002, name: National Institutes of Health; name: Industrial Macromolecular Crystallography Association; DOI: 10.13039/100006151, name: U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, award: DE-AC02-06CH11357; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01 AI109039, P01 AI060699, R01 AI129269; name: KU Endowment Dolph Simons Award in Biomedical Sciences
- Language
- English
- Date published
- 04/25/2018
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
- Record Identifier
- 9983778099902771
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