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

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

Affiliations

  • 1 Arbutus Biopharma, Inc., Warminster, PA, USA. Electronic address: kmcgoverngooch@gmail.com.
  • 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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