@article{03bd32d0348a4971b143055a5dfae43e,
title = "Allosteric inhibitors of the main protease of SARS-CoV-2",
abstract = "SARS-CoV-2 has raised the alarm to search for effective therapy for this virus. To date several vaccines have been approved but few available drugs reported recently still need approval from FDA. Remdesivir was approved for emergency use only. In this report, the SARS-CoV-2 3CLpro was expressed and purified. By using a FRET-based enzymatic assay, we have screened a library consisting of more than 300 different niclosamide derivatives and identified three molecules JMX0286, JMX0301, and JMX0941 as potent allosteric inhibitors against SARS-CoV-2 3CLpro, with IC50 values similar to that of known covalent inhibitor boceprevir. In a cell-based antiviral assay, these inhibitors can inhibit the virus growth with EC50 in the range of 2–3 μM. The mechanism of action of JMX0286, JMX0301, and JMX0941 were characterized by enzyme kinetics, affinity binding and protein-based substrate digestion. Molecular docking, molecular dynamics (MD) simulations and hydration studies suggested that JMX0286, JMX0301, JMX0941 bind specifically to an allosteric pocket of the SARS-CoV-2 3CL protease. This study provides three potent compounds for further studies.",
keywords = "3CLpro, Allosteric inhibitor, Niclosamide, Protease, SARS-CoV-2",
author = "Samrat, {Subodh Kumar} and Jimin Xu and Xuping Xie and Eleonora Gianti and Haiying Chen and Jing Zou and Pattis, {Jason G.} and Khaled Elokely and Hyun Lee and Zhong Li and Klein, {Michael L.} and Shi, {Pei Yong} and Jia Zhou and Hongmin Li",
note = "Funding Information: HL is supported by the NIH grants: AI161845 , AI131669 and AI140406 , and by University of Arizona College of Pharmacy faculty Startup fund, and by R. Ken and Donna Coit Endowed Chair fund in Drug Discovery. Jia Zhou is partly supported by the John D. Stobo, M.D. Distinguished Chair Endowment Fund. P.-Y.S. was supported by NIH grants U19AI171413 and U01AI151801 , and awards from the Sealy & Smith Foundation , the Kleberg Foundation , the John S. Dunn Foundation , the Amon G. Carter Foundation , the Gilson Longenbaugh Foundation , and the Summerfield Robert Foundation . The research conducted at Temple University includes calculations carried out on HPC resources supported in part by the National Science Foundation through major research instrumentation grant number 1625061 and by the US Army Research Laboratory under contract number W911NF-16-2-0189. This project is funded, in part, under a Grant with the Pennsylvania Department of Health (PA CURE). The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. We acknowledge OpenEye Scientific Software for providing the academic license. Publisher Copyright: {\textcopyright} 2022 Elsevier B.V.",
year = "2022",
month = sep,
doi = "10.1016/j.antiviral.2022.105381",
language = "English (US)",
volume = "205",
journal = "Antiviral research",
issn = "0166-3542",
publisher = "Elsevier",
}