Biological characterization of AB-343, a novel and potent SARS-CoV-2 Mpro inhibitor with pan-coronavirus activity

  • Antiviral Res. 2024 Dec:232:106038. doi: 10.1016/j.antiviral.2024.106038.
Kayleigh R McGovern-Gooch  1 ,  Nagraj Mani  2 ,  Dimitar Gotchev  2 ,  Andrzej Ardzinski  2 ,  Rose Kowalski  2 ,  Muhammad Sheraz  2 ,  Holly M Micolochick Steuer  2 ,  Breanna Tercero  2 ,  Xiaohe Wang  2 ,  Adam Wasserman  2 ,  Chia-Yi Chen  3 ,  Konstanze von König  3 ,  Klaus Maskos  3 ,  Archna Prasad  3 ,  Michael Blaesse  3 ,  Andreas Bergmann  3 ,  Debora L Konz Makino  3 ,  Kristi Y Fan  2 ,  Steven G Kultgen  2 ,  Aaron Lindstrom  2 ,  Duyan Nguyen  2 ,  Marvin Vega  2 ,  Xu Wang  2 ,  Nicole Bracci  4 ,  Susan R Weiss  4 ,  Andrew G Cole  2 ,  Angela M Lam  2 ,  Andrea Cuconati  2 ,  Michael J Sofia  2
Affiliations
  • 1. Arbutus Biopharma, Inc., Warminster, PA, USA. Electronic address: [email protected].
  • 2. Arbutus Biopharma, Inc., Warminster, PA, USA.
  • 3. Proteros Biostructures GmbH, D-82152, Martinsried, Germany.
  • 4. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
PMID: 39577571 DOI: 10.1016/j.antiviral.2024.106038
Abstract

Since the SARS-CoV-2 outbreak, there have been ongoing efforts to identify Antiviral molecules with broad coronavirus activity to combat COVID-19. SARS-CoV-2's main Protease (Mpro) is responsible for processing the viral polypeptide into non-structural proteins essential for replication. Here, we present the biological characterization of AB-343, a covalent small-molecule inhibitor of SARS-CoV-2 Mpro with potent activity in both cell-based (EC50 = 0.018 μM) and enzymatic (Ki = 0.0028 μM) assays. AB-343 also demonstrated excellent inhibition of Mpro of other human coronaviruses, including those from the Alpha (229E and NL63) and beta (SARS-CoV, MERS, OC43, and HKU1) families, suggesting the compound could be active against future coronaviruses. No change in AB-343 potency was observed against Mpro of SARS-CoV-2 variants of concern, including Omicron, suggesting that AB-343 could be developed as a treatment against currently circulating coronaviruses. AB-343 also remained active against several Mpro variants which confer significant resistance to nirmatrelvir and ensitrelvir, which are presently the only Mpro inhibitors authorized for the treatment of COVID-19, further supporting the evaluation of AB-343 as a novel and potent therapeutic for COVID-19 and other coronaviruses.

Keywords
AB-343; COVID-19; Coronavirus; M(pro); Resistance; SARS-CoV-2; Variants.
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