Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188

Lockbaum, Gordon J.; Reyes, Archie C.; Lee, Jeong Min; Tilvawala, Ronak; Nalivaika, Ellen A.; Ali, Akbar; Kurt Yilmaz, Nese; Thompson, Paul R.; Schiffer, Celia A.

doi:10.3390/v13020174

Open AccessArticle

Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188

by

Gordon J. Lockbaum

,

Archie C. Reyes

,

Jeong Min Lee

,

Ronak Tilvawala

,

Ellen A. Nalivaika

,

Akbar Ali

,

Nese Kurt Yilmaz

,

Paul R. Thompson

and

Celia A. Schiffer

^*

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA

^*

Author to whom correspondence should be addressed.

Viruses 2021, 13(2), 174; https://doi.org/10.3390/v13020174

Submission received: 24 December 2020 / Revised: 15 January 2021 / Accepted: 17 January 2021 / Published: 25 January 2021

(This article belongs to the Special Issue In Memory of Stephen Oroszlan)

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Abstract

Viral proteases are critical enzymes for the maturation of many human pathogenic viruses and thus are key targets for direct acting antivirals (DAAs). The current viral pandemic caused by SARS-CoV-2 is in dire need of DAAs. The Main protease (M^pro) is the focus of extensive structure-based drug design efforts which are mostly covalent inhibitors targeting the catalytic cysteine. ML188 is a non-covalent inhibitor designed to target SARS-CoV-1 M^pro, and provides an initial scaffold for the creation of effective pan-coronavirus inhibitors. In the current study, we found that ML188 inhibits SARS-CoV-2 M^pro at 2.5 µM, which is more potent than against SAR-CoV-1 M^pro. We determined the crystal structure of ML188 in complex with SARS-CoV-2 M^pro to 2.39 Å resolution. Sharing 96% sequence identity, structural comparison of the two complexes only shows subtle differences. Non-covalent protease inhibitors complement the design of covalent inhibitors against SARS-CoV-2 main protease and are critical initial steps in the design of DAAs to treat CoVID 19.

Keywords: SARS-CoV-2; Covid-19; main protease; M^pro; ML188; protease inhibitor; crystal structure; structure-based drug design; direct-acting antivirals

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MDPI and ACS Style

Lockbaum, G.J.; Reyes, A.C.; Lee, J.M.; Tilvawala, R.; Nalivaika, E.A.; Ali, A.; Kurt Yilmaz, N.; Thompson, P.R.; Schiffer, C.A. Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188. Viruses 2021, 13, 174. https://doi.org/10.3390/v13020174

AMA Style

Lockbaum GJ, Reyes AC, Lee JM, Tilvawala R, Nalivaika EA, Ali A, Kurt Yilmaz N, Thompson PR, Schiffer CA. Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188. Viruses. 2021; 13(2):174. https://doi.org/10.3390/v13020174

Chicago/Turabian Style

Lockbaum, Gordon J., Archie C. Reyes, Jeong Min Lee, Ronak Tilvawala, Ellen A. Nalivaika, Akbar Ali, Nese Kurt Yilmaz, Paul R. Thompson, and Celia A. Schiffer. 2021. "Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188" Viruses 13, no. 2: 174. https://doi.org/10.3390/v13020174

APA Style

Lockbaum, G. J., Reyes, A. C., Lee, J. M., Tilvawala, R., Nalivaika, E. A., Ali, A., Kurt Yilmaz, N., Thompson, P. R., & Schiffer, C. A. (2021). Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188. Viruses, 13(2), 174. https://doi.org/10.3390/v13020174

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Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188

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