tetano
Editor, Senior Moderator
Antiviral Res
. 2024 Nov 20:106038.
doi: 10.1016/j.antiviral.2024.106038. Online ahead of print. Biological Characterization of AB-343, a Novel and Potent SARS-CoV-2 M[SUP]pro[/SUP] Inhibitor with Pan-Coronavirus Activity
Kayleigh R McGovern-Gooch[SUP] 1 [/SUP], Nagraj Mani[SUP] 2 [/SUP], Dimitar Gotchev[SUP] 2 [/SUP], Andrzej Ardzinski[SUP] 2 [/SUP], Rose Kowalski[SUP] 2 [/SUP], Muhammad Sheraz[SUP] 2 [/SUP], Holly M Micolochick Steuer[SUP] 2 [/SUP], Breanna Tercero[SUP] 2 [/SUP], Xiaohe Wang[SUP] 2 [/SUP], Adam Wasserman[SUP] 2 [/SUP], Chia-Yi Chen[SUP] 3 [/SUP], Konstanze von König[SUP] 3 [/SUP], Klaus Maskos[SUP] 3 [/SUP], Archna Prasad[SUP] 3 [/SUP], Michael Blaesse[SUP] 3 [/SUP], Andreas Bergmann[SUP] 3 [/SUP], Debora L Konz Makino[SUP] 3 [/SUP], Kristi Y Fan[SUP] 2 [/SUP], Steven G Kultgen[SUP] 2 [/SUP], Aaron Lindstrom[SUP] 2 [/SUP], Duyan Nguyen[SUP] 2 [/SUP], Marvin Vega[SUP] 2 [/SUP], Xu Wang[SUP] 2 [/SUP], Nicole Bracci[SUP] 4 [/SUP], Susan R Weiss[SUP] 4 [/SUP], Andrew G Cole[SUP] 2 [/SUP], Angela M Lam[SUP] 2 [/SUP], Andrea Cuconati[SUP] 2 [/SUP], Michael J Sofia[SUP] 2 [/SUP]
Affiliations
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[SUP]pro[/SUP]) 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[SUP]pro[/SUP] with potent activity in both cell-based (EC[SUB]50[/SUB] = 0.018 μM) and enzymatic (K[SUB]i[/SUB] = 0.0028 μM) assays. AB-343 also demonstrated excellent inhibition of M[SUP]pro[/SUP] 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[SUP]pro[/SUP] 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[SUP]pro[/SUP] variants which confer significant resistance to nirmatrelvir and ensitrelvir, which are presently the only M[SUP]pro[/SUP] 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; M(pro); SARS-CoV-2; coronavirus; resistance; variants.
. 2024 Nov 20:106038.
doi: 10.1016/j.antiviral.2024.106038. Online ahead of print. Biological Characterization of AB-343, a Novel and Potent SARS-CoV-2 M[SUP]pro[/SUP] Inhibitor with Pan-Coronavirus Activity
Kayleigh R McGovern-Gooch[SUP] 1 [/SUP], Nagraj Mani[SUP] 2 [/SUP], Dimitar Gotchev[SUP] 2 [/SUP], Andrzej Ardzinski[SUP] 2 [/SUP], Rose Kowalski[SUP] 2 [/SUP], Muhammad Sheraz[SUP] 2 [/SUP], Holly M Micolochick Steuer[SUP] 2 [/SUP], Breanna Tercero[SUP] 2 [/SUP], Xiaohe Wang[SUP] 2 [/SUP], Adam Wasserman[SUP] 2 [/SUP], Chia-Yi Chen[SUP] 3 [/SUP], Konstanze von König[SUP] 3 [/SUP], Klaus Maskos[SUP] 3 [/SUP], Archna Prasad[SUP] 3 [/SUP], Michael Blaesse[SUP] 3 [/SUP], Andreas Bergmann[SUP] 3 [/SUP], Debora L Konz Makino[SUP] 3 [/SUP], Kristi Y Fan[SUP] 2 [/SUP], Steven G Kultgen[SUP] 2 [/SUP], Aaron Lindstrom[SUP] 2 [/SUP], Duyan Nguyen[SUP] 2 [/SUP], Marvin Vega[SUP] 2 [/SUP], Xu Wang[SUP] 2 [/SUP], Nicole Bracci[SUP] 4 [/SUP], Susan R Weiss[SUP] 4 [/SUP], Andrew G Cole[SUP] 2 [/SUP], Angela M Lam[SUP] 2 [/SUP], Andrea Cuconati[SUP] 2 [/SUP], Michael J Sofia[SUP] 2 [/SUP]
Affiliations
- PMID: 39577571
- DOI: 10.1016/j.antiviral.2024.106038
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[SUP]pro[/SUP]) 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[SUP]pro[/SUP] with potent activity in both cell-based (EC[SUB]50[/SUB] = 0.018 μM) and enzymatic (K[SUB]i[/SUB] = 0.0028 μM) assays. AB-343 also demonstrated excellent inhibition of M[SUP]pro[/SUP] 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[SUP]pro[/SUP] 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[SUP]pro[/SUP] variants which confer significant resistance to nirmatrelvir and ensitrelvir, which are presently the only M[SUP]pro[/SUP] 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; M(pro); SARS-CoV-2; coronavirus; resistance; variants.