@article{3c2a5f71ea07452fb3e3585596e0fd1b,
title = "A Quick Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors**",
abstract = "The COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2MPro) to digest two of its translated long polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replicating in infected cells and therefore provides a potential COVID-19 treatment option. Guided by previous medicinal chemistry studies about SARS-CoV-1 main protease (SC1MPro), we have designed and synthesized a series of SC2MPro inhibitors that contain β-(S-2-oxopyrrolidin-3-yl)-alaninal (Opal) for the formation of a reversible covalent bond with the SC2MPro active-site cysteine C145. All inhibitors display high potency with Ki values at or below 100 nM. The most potent compound, MPI3, has as a Ki value of 8.3 nM. Crystallographic analyses of SC2MPro bound to seven inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accommodate the inhibitors. Virus inhibition assays revealed that several inhibitors have high potency in inhibiting the SARS-CoV-2-induced cytopathogenic effect in both Vero E6 and A549/ACE2 cells. Two inhibitors, MPI5 and MPI8, completely prevented the SARS-CoV-2-induced cytopathogenic effect in Vero E6 cells at 2.5–5 μM and A549/ACE2 cells at 0.16–0.31 μM. Their virus inhibition potency is much higher than that of some existing molecules that are under preclinical and clinical investigations for the treatment of COVID-19. Our study indicates that there is a large chemical space that needs to be explored for the development of SC2MPro inhibitors with ultra-high antiviral potency.",
keywords = "3C-like protease, COVID-19, SARS-CoV-2, antivirals, main protease, reversible covalent inhibitors",
author = "Yang, {Kai S.} and Ma, {Xinyu R.} and Yuying Ma and Alugubelli, {Yugendar R.} and Scott, {Danielle A.} and Vatansever, {Erol C.} and Drelich, {Aleksandra K.} and Banumathi Sankaran and Geng, {Zhi Z.} and Blankenship, {Lauren R.} and Ward, {Hannah E.} and Sheng, {Yan J.} and Hsu, {Jason C.} and Kratch, {Kaci C.} and Baoyu Zhao and Hayatshahi, {Hamed S.} and Jin Liu and Pingwei Li and Fierke, {Carol A.} and Tseng, {Chien Te K.} and Shiqing Xu and Liu, {Wenshe Ray}",
note = "Funding Information: This work was supported in part by National Institutes of Health (R01 GM121584 to W.R.L. and grant R01AI145287 to P.L.), Welch Foundation (grant A‐1715 to W.R.L. and grant A‐1987 to C.A.F.), Texas A&M University X Grant Mechanism, Texas A&M University Translational Investment Fund, the Texas A&M University President's Excellence Fund, and Texas A&M University Strategic Transformative Research Program. We are grateful to Prof. Thomas Meek for allowing us to use the LC–MS system in his group for purification and characterization of some of our compounds. The ALS‐ENABLE beam‐lines are supported in part by the National Institutes of Health, National Institute of General Medical Sciences, grant P30 GM124169‐01 and the Howard Hughes Medical Institute. The Advanced Light Source is a Department of Energy Office of Science User Facility under Contract No. DE‐AC02‐05CH11231. Funding Information: This work was supported in part by National Institutes of Health (R01 GM121584 to W.R.L. and grant R01AI145287 to P.L.), Welch Foundation (grant A-1715 to W.R.L. and grant A-1987 to C.A.F.), Texas A&M University X Grant Mechanism, Texas A&M University Translational Investment Fund, the Texas A&M University President's Excellence Fund, and Texas A&M University Strategic Transformative Research Program. We are grateful to Prof. Thomas Meek for allowing us to use the LC?MS system in his group for purification and characterization of some of our compounds. The ALS-ENABLE beam-lines are supported in part by the National Institutes of Health, National Institute of General Medical Sciences, grant P30 GM124169-01 and the Howard Hughes Medical Institute. The Advanced Light Source is a Department of Energy Office of Science User Facility under Contract No. DE-AC02-05CH11231. Publisher Copyright: {\textcopyright} 2020 Wiley-VCH GmbH",
year = "2021",
month = mar,
day = "18",
doi = "10.1002/cmdc.202000924",
language = "English",
volume = "16",
pages = "942--948",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "John Wiley and Sons Ltd",
number = "6",
}