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- Title
Exploiting Hydrophobic Amino Acid Scanning to Develop Cyclic Peptide Inhibitors of the SARS‐CoV‐2 Main Protease with Antiviral Activity.
- Authors
Harrison, Katriona; Carlos, Patrick W.; Ullrich, Sven; Aggarwal, Anupriya; Johansen‐Leete, Jason; Sasi, Vishnu Mini; Barter, Isabel; Maxwell, Joshua W. C.; Bedding, Max J.; Larance, Mark; Turville, Stuart; Norman, Alexander; Jackson, Colin J.; Nitsche, Christoph; Payne, Richard J.
- Abstract
The development of novel antivirals is crucial not only for managing current COVID‐19 infections but for addressing potential future zoonotic outbreaks. SARS‐CoV‐2 main protease (Mpro) is vital for viral replication and viability and therefore serves as an attractive target for antiviral intervention. Herein, we report the optimization of a cyclic peptide inhibitor that emerged from an mRNA display selection against the SARS‐CoV‐2 Mpro to enhance its cell permeability and in vitro antiviral activity. By identifying mutation‐tolerant amino acid residues within the peptide sequence, we describe the development of a second‐generation Mpro inhibitor bearing five cyclohexylalanine residues. This cyclic peptide analogue exhibited significantly improved cell permeability and antiviral activity compared to the parent peptide. This approach highlights the importance of optimizing cyclic peptide hits for activity against intracellular targets such as the SARS‐CoV‐2 Mpro.
- Subjects
AMINO acid residues; CYCLIC peptides; PEPTIDES; AMINO acid sequence; CELL permeability
- Publication
Chemistry - A European Journal, 2024, Vol 30, Issue 44, p1
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.202401606