Poster Presentation International Peptide Symposium 2023

Development of Antiviral Cyclic Peptides Targeting the Main Protease of SARS-CoV-2 (#246)

Kat Harrison 1 2 , Jason Johansen-Leete 1 2 , Sven Ullrich 3 , Sarah E. Fry 1 2 , Rebecca Frkic 3 4 , Max J. Bedding 1 2 , Anupriya Aggarwal 5 , Toby Passioura 1 2 , Stuart Turville 5 , Colin J. Jackson 3 4 , Christoph Nitsche 3 , Richard J. Payne 1 2
  1. School of Chemistry, The University of Sydney, Camperdown, NSW, Australia
  2. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, NSW, Australia
  3. Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia
  4. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University, Canberra, ACT , Australia
  5. The Kirby Institute, The University of New South Wales, Kensington, NSW 2052, Australia

Effective antivirals are essential for the continued control of the COVID-19 pandemic and to complement existing vaccines. The SARS-CoV-2 main protease (Mpro) is a highly conserved functional protein that is essential for viral replication and proliferation in the host.1 With an indispensable role in the viral lifecycle and unique specificity, relative to host enzymes, Mpro is a very attractive target for the development of antiviral therapeutics to combat the COVID-19 pandemic.2 Indeed, Nirmatrelvir (Pfizer), the first approved antiviral that was specifically designed against the SARS-CoV-2 virus, inhibits Mpro.3

In this poster I will detail the development of high affinity ligands for the SARS-CoV-2 Mpro using the Random nonstandard Peptide Integrated Discovery (RaPID) mRNA display technology on a chemically cross-linked SARS-CoV-2 dimer.3 This technique identified several high-affinity cyclic peptides that were potent inhibitors of the catalytic activity of the protease.4 These parent molecules also exhibited in vitro antiviral activity against SARS-CoV-2 with EC50 values, albeit in the low micromolar range. These cyclic peptides have served as a template for further modifications to optimise cell permeability and, therefore, antiviral activity.

  1. V’kovski, P., Kratzel, A., Steiner, S., Stalder, H. & Thiel, V. Nat. Rev. Microbiol. 19, 155–170, (2021).
  2. Ullrich, S. & Nitsche, C. Bioorg. Med. Chem. Lett. 30, 127377 (2020).
  3. Owen, D. R., et al. Science, 374, 1586-1593, (2021).
  4. Johansen-Leete, J. et al., Chem. Sci., 2022, 13, 3826-3836 (2023).