Exploiting Hydrophobic Amino Acid Scanning to Develop Cyclic Peptide Inhibitors of the SARS-CoV-2 Main Protease with Antiviral Activity

Katriona Harrison; Patrick W Carlos; Sven Ullrich; Anupriya Aggarwal; Jason Johansen-Leete; Vishnu Mini Sasi; Isabel Barter; Joshua W C Maxwell; Max J Bedding; Mark Larance; Stuart Turville; Alexander Norman; Colin J Jackson; Christoph Nitsche; Richard J Payne

doi:10.1002/chem.202401606

Exploiting Hydrophobic Amino Acid Scanning to Develop Cyclic Peptide Inhibitors of the SARS-CoV-2 Main Protease with Antiviral Activity

Chemistry. 2024 Aug 6;30(44):e202401606. doi: 10.1002/chem.202401606. Epub 2024 Jul 17.

Authors

Katriona Harrison^{1

2}, Patrick W Carlos^{1

2}, Sven Ullrich³, Anupriya Aggarwal⁴, Jason Johansen-Leete^{1

2}, Vishnu Mini Sasi^{3

5}, Isabel Barter^{1

2

6

7}, Joshua W C Maxwell^{1

2}, Max J Bedding^{1

2}, Mark Larance^{6

7}, Stuart Turville⁴, Alexander Norman^{1

2}, Colin J Jackson^{3

5}, Christoph Nitsche³, Richard J Payne^{1

2}

Affiliations

¹ School of Chemistry, The University of Sydney, Sydney, NSW, 2006, Australia.
² Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney, NSW, 2006, Australia.
³ Research School of Chemistry, Australian National University, Canberra, ACT, 2601, Australia.
⁴ The Kirby Institute, University of New South Wales, Sydney, NSW, 2052, Australia.
⁵ Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University, Canberra, ACT, 2601, Australia.
⁶ Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.
⁷ School of Medical Sciences, The University of Sydney, Sydney, NSW, 2006, Australia.

PMID: 38801240
DOI: 10.1002/chem.202401606

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 (M^pro) 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 M^pro 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 M^pro 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 M^pro.

Keywords: Antiviral agents; COVID-19; Cyclic peptides; Main protease; SARS-CoV-2.

MeSH terms

Amino Acids / chemistry
Antiviral Agents* / chemistry
Antiviral Agents* / pharmacology
COVID-19 Drug Treatment
Coronavirus 3C Proteases* / antagonists & inhibitors
Coronavirus 3C Proteases* / chemistry
Coronavirus 3C Proteases* / metabolism
Humans
Hydrophobic and Hydrophilic Interactions*
Peptides, Cyclic* / chemistry
Peptides, Cyclic* / pharmacology
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology
SARS-CoV-2* / drug effects
SARS-CoV-2* / enzymology

Substances

Peptides, Cyclic
Antiviral Agents
Coronavirus 3C Proteases
Protease Inhibitors
Amino Acids
3C-like proteinase, SARS-CoV-2

Abstract

MeSH terms

Substances

Grants and funding