| Autor: |
Rebecca L. Frkic, Sarah E. Fry, Anneliese S. Ashhurst, Colin J. Jackson, Mithun C. Mahawaththa, Kasuni B Ekanayake, Anupriya Aggarwal, Gottfried Otting, Toby Passioura, Stuart Turville, Christoph Nitsche, Mark Larance, Vishnu M. Sasi, Sven Ullrich, Max J. Bedding, Richard J. Payne, Jason Johansen-Leete |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
Antivirals that specifically target SARS-CoV-2 are needed to control the COVID-19 pandemic. The main protease (Mpro) 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 Mpro dimer, which yielded several high-affinity thioether-linked cyclic peptide inhibitors of the protease. Structural analysis of Mpro 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 Mpro peptide inhibitors possessed antiviral activity against SARS-CoV-2 in vitro with EC50 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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