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

Galasiti Kankanamalage, Anushka C.; Kim, Yunjeong; Damalanka, Vishnu C.; Rathnayake, Athri D.; Fehr, Anthony R.; Mehzabeen, Nurjahan; Battaile, Kevin P.; Lovell, Scott; Lushington, Gerald H.; Perlman, Stanley; Chang, Kyeong-Ok; Groutas, William C.

doi:10.1016/j.ejmech.2018.03.004

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

Journal Article · Tue Mar 06 00:00:00 EST 2018 · European Journal of Medicinal Chemistry

DOI:https://doi.org/10.1016/j.ejmech.2018.03.004· OSTI ID:1433721

^[1];

^[2]; Damalanka, Vishnu C. ^[1]; Rathnayake, Athri D. ^[1]; Fehr, Anthony R. ^[3]; Mehzabeen, Nurjahan ^[4]; Battaile, Kevin P. ^[5]; Lovell, Scott ^[4]; Lushington, Gerald H. ^[6]; Perlman, Stanley ^[3]; Chang, Kyeong-Ok ^[2];

^[1]

Wichita State Univ., Wichita, KS (United States)
Kansas State Univ., Manhattan, KS (United States)
Univ. of Iowa, Iowa City, IA (United States). Carver College of Medicine
Univ. of Kansas, Lawrence, KS (United States)
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
LiS Consulting, Lawrence, KS (United States)

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. Additionally, the mechanism of action of the compounds and the structural determinants associated with binding were illuminated using X-ray crystallography.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); Industrial Macromolecular Crystallography Association; KU Endowment Dolph Simons Award in Biomedical Sciences

Grant/Contract Number:: AC02-06CH11357; P30GM110761; R01 AI109039; P01 AI060699; R01 AI129269

OSTI ID:: 1433721

Alternate ID(s):: OSTI ID: 1548593

Journal Information:: European Journal of Medicinal Chemistry, Vol. 150, Issue C; ISSN 0223-5234

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 75 works

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Piperidine carbamate peptidomimetic inhibitors of the serine proteases HGFA, matriptase and hepsin Damalanka, Vishnu C.; Wildman, Scott A.; Janetka, James W. MedChemComm, Vol. 10, Issue 9 https://doi.org/10.1039/c9md00234k	journal	January 2019
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Structural Genomics of SARS-CoV-2 Indicates Evolutionary Conserved Functional Regions of Viral Proteins Srinivasan, Suhas; Cui, Hongzhu; Gao, Ziyang Viruses, Vol. 12, Issue 4 https://doi.org/10.3390/v12040360	journal	March 2020
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60 APPLIED LIFE SCIENCES
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Antiviral
Peptidomimetic inhibitors

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

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