2. Academic Validation
  3. A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants

A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants

  • Emerg Microbes Infect. 2023 Dec;12(2):2246594. doi: 10.1080/22221751.2023.2246594.
Jimena Pérez-Vargas 1,  Liam J Worrall 2,  Andrea D Olmstead 1,  Anh-Tien Ton 3,  Jaeyong Lee 2 4,  Ivan Villanueva 1,  Connor A H Thompson 1,  Svenja Dudek 1,  Siobhan Ennis 5,  Jason R Smith 3 6,  Tirosh Shapira 1,  Joshua De Guzman 1,  Shutong Gang 1,  Fuqiang Ban 3,  Marija Vuckovic 2,  Michael Bielecki 6,  Suzana Kovacic 6,  Calem Kenward 2,  Christopher Yee Hong 1,  Danielle G Gordon 1,  Paul N Levett 7 8,  Mel Krajden 7 8,  Richard Leduc 9,  Pierre-Luc Boudreault 9,  Masahiro Niikura 5,  Mark Paetzel 4,  Robert N Young 6,  Artem Cherkasov 3,  Natalie C J Strynadka 2,  François Jean 1
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, Canada.
  • 2 Department of Biochemistry and Molecular Biology and Centre for Blood Research, University of British Columbia, Vancouver, Canada.
  • 3 Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.
  • 4 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada.
  • 5 Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
  • 6 Department of Chemistry, Simon Fraser University, Burnaby, Canada.
  • 7 British Columbia Centre for Disease Control Public Health Laboratory, Vancouver, Canada.
  • 8 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
  • 9 Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Canada.
PMID: 37555275 DOI: 10.1080/22221751.2023.2246594
Abstract

Antivirals with broad coronavirus activity are important for treating high-risk individuals exposed to the constantly evolving SARS-CoV-2 variants of concern (VOCs) as well as emerging drug-resistant variants. We developed and characterized a novel class of active-site-directed 3-chymotrypsin-like protease (3CLpro) inhibitors (C2-C5a). Our lead direct-acting Antiviral (DAA), C5a, is a non-covalent, non-peptide with a dissociation constant of 170 nM against recombinant SARS-CoV-2 3CLpro. The compounds C2-C5a exhibit broad-spectrum activity against Omicron subvariants (BA.5, BQ.1.1, and XBB.1.5) and seasonal human coronavirus-229E Infection in human cells. Notably, C5a has median effective concentrations of 30-50 nM against BQ.1.1 and XBB.1.5 in two different human cell lines. X-ray crystallography has confirmed the unique binding modes of C2-C5a to the 3CLpro, which can limit virus cross-resistance to emerging Paxlovid-resistant variants. We tested the effect of C5a with two of our newly discovered host-directed antivirals (HDAs): N-0385, a TMPRSS2 inhibitor, and bafilomycin D (BafD), a human vacuolar H+-ATPase [V-ATPase] inhibitor. We demonstrated a synergistic action of C5a in combination with N-0385 and BafD against Omicron BA.5 Infection in human Calu-3 lung cells. Our findings underscore that a SARS-CoV-2 multi-targeted treatment for circulating Omicron subvariants based on DAAs (C5a) and HDAs (N-0385 or BafD) can lead to therapeutic benefits by enhancing treatment efficacy. Furthermore, the high-resolution structures of SARS-CoV-2 3CLpro in complex with C2-C5a will facilitate future rational optimization of our novel broad-spectrum active-site-directed 3C-like Protease Inhibitors.

Keywords

3CLpro inhibitor; SARS-CoV-2 3CLpro; SARS-CoV-2 Omicron subvariants; combination therapy; computer-aided drug design.

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