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

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.

View Accepted Manuscript (DOE)

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

Sponsoring Organization:: Industrial Macromolecular Crystallography Association; KU Endowment Dolph Simons Award in Biomedical Sciences; National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1433721

Alternate ID(s):: OSTI ID: 1548593

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

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Molecular Characteristics, Functions, and Related Pathogenicity of MERS-CoV Proteins Li, Yan-Hua; Hu, Chen-Yu; Wu, Nan-Ping Engineering, Vol. 5, Issue 5 https://doi.org/10.1016/j.eng.2018.11.035	journal	October 2019
Development of Small-Molecule MERS-CoV Inhibitors Liang, Ruiying; Wang, Lili; Zhang, Naru Viruses, Vol. 10, Issue 12 https://doi.org/10.3390/v10120721	journal	December 2018
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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
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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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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References (53)

Cited By (6)

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