Exploiting Hydrophobic Amino Acid Scanning to Develop Cyclic Peptide Inhibitors of the SARS-CoV-2 Main Protease with Antiviral Activity.
Chemistry
; 30(44): e202401606, 2024 Aug 06.
Article
in En
| MEDLINE
| ID: mdl-38801240
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 inâ
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Peptides, Cyclic
/
Hydrophobic and Hydrophilic Interactions
/
Coronavirus 3C Proteases
/
SARS-CoV-2
Limits:
Humans
Language:
En
Journal:
Chemistry
Journal subject:
QUIMICA
Year:
2024
Type:
Article
Affiliation country:
Australia