7LKE

X-ray crystal structure of the SARS-CoV-2 main protease in space group C2

Summary for 7LKE

• Entry DOI: 10.2210/pdb7lke/pdb
• Related: 7LBN
• Descriptor: 3C-like proteinase (1 entity in total)
• Functional Keywords: protease, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV,SARS-CoV-2)
• Total number of polymer chains: 1
• Total formula weight: 33825.55

Authors

Narwal, M.,Murakami, K.S. (deposition date: 2021-02-02, release date: 2021-04-14, Last modification date: 2023-10-18)

Primary citation

Narayanan, A.,Narwal, M.,Majowicz, S.A.,Varricchio, C.,Toner, S.A.,Ballatore, C.,Brancale, A.,Murakami, K.S.,Jose, J.
Identification of SARS-CoV-2 inhibitors targeting Mpro and PLpro using in-cell-protease assay.
Commun Biol, 5:169-169, 2022

PubMed Abstract: SARS-CoV-2 proteases Mpro and PLpro are promising targets for antiviral drug development. In this study, we present an antiviral screening strategy involving a novel in-cell protease assay, antiviral and biochemical activity assessments, as well as structural determinations for rapid identification of protease inhibitors with low cytotoxicity. We identified eight compounds with anti-SARS-CoV-2 activity from a library of 64 repurposed drugs and modeled at protease active sites by in silico docking. We demonstrate that Sitagliptin and Daclatasvir inhibit PLpro, and MG-101, Lycorine HCl, and Nelfinavir mesylate inhibit Mpro of SARS-CoV-2. The X-ray crystal structure of Mpro in complex with MG-101 shows a covalent bond formation between the inhibitor and the active site Cys145 residue indicating its mechanism of inhibition is by blocking the substrate binding at the active site. Thus, we provide methods for rapid and effective screening and development of inhibitors for blocking virus polyprotein processing as SARS-CoV-2 antivirals. Additionally, we show that the combined inhibition of Mpro and PLpro is more effective in inhibiting SARS-CoV-2 and the delta variant.

PubMed: 35217718
DOI: 10.1038/s42003-022-03090-9

Experimental method

X-RAY DIFFRACTION (2.69 Å)