McGovern-Gooch Kayleigh R, Mani Nagraj, Gotchev Dimitar, Ardzinski Andrzej, Kowalski Rose, Sheraz Muhammad, Micolochick Steuer Holly M, Tercero Breanna, Wang Xiaohe, Wasserman Adam, Chen Chia-Yi, von König Konstanze, Maskos Klaus, Prasad Archna, Blaesse Michael, Bergmann Andreas, Konz Makino Debora L, Fan Kristi Y, Kultgen Steven G, Lindstrom Aaron, Nguyen Duyan, Vega Marvin, Wang Xu, Bracci Nicole, Weiss Susan R, Cole Andrew G, Lam Angela M, Cuconati Andrea, Sofia Michael J
Arbutus Biopharma, Inc., Warminster, PA, USA.
Arbutus Biopharma, Inc., Warminster, PA, USA.
Antiviral Res. 2024 Dec;232:106038. doi: 10.1016/j.antiviral.2024.106038. Epub 2024 Nov 20.
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 (M) 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 M with potent activity in both cell-based (EC = 0.018 μM) and enzymatic (K = 0.0028 μM) assays. AB-343 also demonstrated excellent inhibition of M 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 M 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 M variants which confer significant resistance to nirmatrelvir and ensitrelvir, which are presently the only M 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.
自新冠病毒（SARS-CoV-2）疫情爆发以来，人们一直在努力寻找具有广泛冠状病毒活性的抗病毒分子，以对抗新冠肺炎。SARS-CoV-2的主要蛋白酶（M）负责将病毒多肽加工成复制所必需的非结构蛋白。在此，我们展示了AB-343的生物学特性，它是一种共价小分子SARS-CoV-2 M抑制剂，在基于细胞的实验（EC = 0.018 μM）和酶实验（K = 0.0028 μM）中均具有强大活性。AB-343对其他人类冠状病毒的M也表现出优异的抑制作用，包括来自α（229E和NL63）和β（SARS-CoV、MERS、OC43和HKU1）家族的病毒，这表明该化合物可能对未来的冠状病毒也有活性。针对包括奥密克戎在内的SARS-CoV-2变异株的M，未观察到AB-343的效力发生变化，这表明AB-343可被开发用于治疗当前正在传播的冠状病毒。AB-343对几种对奈玛特韦和恩西他韦具有显著抗性的M变异株也保持活性，奈玛特韦和恩西他韦是目前唯一被批准用于治疗新冠肺炎的M抑制剂，这进一步支持将AB-343评估为一种针对新冠肺炎和其他冠状病毒的新型强效治疗药物。
