Poster Presentation 14th Australian Peptide Conference 2022

Antiviral Cyclic Peptides Targeting the Main Protease of SARS-CoV-2 (#139)

Patrick Carlos 1 , Jason Johansen-Leete 2 , Sven Ullrich 3 , Sarah E Fry 2 , Rebecca Frkic 3 , Max J Bedding 2 , Anupriya Aggarwal 4 , Anneliese S Ashhurst 2 , Toby Passioura 2 5 , Stuart Turville 4 , Colin J Jackson 3 , Christoph Nitsche 3 , Richard J Payne 2
  1. University of Sydney, Ingleburn, NSW, Australia
  2. School of Chemistry and Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney
  3. Research School of Chemistry, Australian National University, Canberra
  4. Kirby Institute, Sydney
  5. Sydney Analytical, The University of Sydney, Sydney

Antiviral therapeutics that target SARS-CoV-2 activity are a critical tool to control the COVID-19 pandemic and necessary to complement the vaccine effort. An effective antiviral must elicit potent activity against the target without inducing deleterious side-effects. A desirable target for the development of SARS-CoV-2 therapeutics is the main protease (Mpro), a highly conserved functional protein required for SARS-CoV-2 viral replication and proliferation in the host.1 With an indispensable role in the viral lifecycle and unique specificity, relative to host enzymes, the Mpro is an attractive target for the development of antiviral therapeutics to combat the COVID-19 pandemic.1-3 

 

We have performed Random nonstandard Peptide Integrated Discovery (RaPID) mRNA display against a chemically-cross linked SARS-CoV-2 Mpro dimer, which returned several high-affinity thioether-linked cyclic peptide inhibitors of the target in vitro.4-7 Structural analysis of the Mpro complexed with a selenoether analogue of the most potent inhibitor revealed fundamental binding interactions responsible for activity; a glutamine and leucine residue in the S1 and S2 sites respectively, in concert with a binding configuration that straddles both chains of the physiological dimer. Structure-activity relationships of several of the lead Mpro inhibitors were probed with a series of alanine analogues. When assessed in vivo, several of the Mpro inhibitors exhibited antiviral activity against SARS-CoV-2 with EC50 values in the low micromolar range that could be enhanced further with the appendage of a cell-penetrating peptide. Collectively, these cyclic peptide Mpro inhibitors provide a promising foundation for the development of antiviral therapeutics specific to SARS-CoV-2.

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