7RNW

SARS-CoV-2 Main Protease in complex with a cyclic peptide inhibitor

Summary for 7RNW

• Entry DOI: 10.2210/pdb7rnw/pdb
• Descriptor: 3C-like proteinase, ACE-DTY-LEU-GLN-TYR-ALA-VAL-LEU-ARG-HIS-LYS-ARG-ARG-GLU-SEC (3 entities in total)
• Functional Keywords: protease, drug design, complex, covid-19, viral protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2); More
• Total number of polymer chains: 8
• Total formula weight: 142950.70

Authors

Frkic, R.L.,Jackson, C.J. (deposition date: 2021-07-30, release date: 2022-03-16, Last modification date: 2023-10-18)

Primary citation

Johansen-Leete, J.,Ullrich, S.,Fry, S.E.,Frkic, R.,Bedding, M.J.,Aggarwal, A.,Ashhurst, A.S.,Ekanayake, K.B.,Mahawaththa, M.C.,Sasi, V.M.,Luedtke, S.,Ford, D.J.,O'Donoghue, A.J.,Passioura, T.,Larance, M.,Otting, G.,Turville, S.,Jackson, C.J.,Nitsche, C.,Payne, R.J.
Antiviral cyclic peptides targeting the main protease of SARS-CoV-2.
Chem Sci, 13:3826-3836, 2022

PubMed Abstract: Antivirals that specifically target SARS-CoV-2 are needed to control the COVID-19 pandemic. The main protease (M) is essential for SARS-CoV-2 replication and is an attractive target for antiviral development. Here we report the use of the Random nonstandard Peptide Integrated Discovery (RaPID) mRNA display on a chemically cross-linked SARS-CoV-2 M dimer, which yielded several high-affinity thioether-linked cyclic peptide inhibitors of the protease. Structural analysis of M complexed with a selenoether analogue of the highest-affinity peptide revealed key binding interactions, including glutamine and leucine residues in sites S1 and S2, respectively, and a binding epitope straddling both protein chains in the physiological dimer. Several of these M peptide inhibitors possessed antiviral activity against SARS-CoV-2 with EC values in the low micromolar range. These cyclic peptides serve as a foundation for the development of much needed antivirals that specifically target SARS-CoV-2.

PubMed: 35432913
DOI: 10.1039/d1sc06750h

Experimental method

X-RAY DIFFRACTION (2.35 Å)