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<p>The 2019 pandemic of coronavirus disease (COVID-19) caused by SARS-CoV-2 led to millions of deaths worldwide since its emergence. The viral genomic material can code structural and non-structural proteins including the main protease or 3CL<sup>pro</sup>, a cysteine protease that cleavages the viral polyprotein generating 11 proteins that participate in viral pre-replication. Thus, 3CL<sup>pro</sup> is a promising therapeutic target for SARS-CoV-2 inhibition by new drugs or drug repositioning because 3CL<sup>pro</sup> is dissimilar to human proteases. We conducted in vitro assays demonstrating the modulation activity of ambenonium, a drug already used in <i>Myasthenia gravis</i> that acts by inhibiting the action of acetylcholinesterase, and had its potential inhibitory activity against viral replication pointed out in a previous in silico study. In concentrations of 100&#xa0;µM, 50&#xa0;µM, 25&#xa0;µM, 10&#xa0;µM, and 1&#xa0;µM there was no inhibition in the formation of lysis plates, with a slight increase in the genome copy number at the higher concentrations evaluated. However, in the concentrations of 0,1&#xa0;µM and 0,01&#xa0;µM, there was a reduction in the number of lysis plates. This behavior suggests that the ambenonium acts as a modulator of viral activity in vitro. To investigate potential conformational changes in the protein between dimeric and monomeric forms in the presence of the compound, a local docking analysis was performed. Results indicated this conformational shift is possible, though further studies are needed to confirm these findings.</p>

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In vitro enzymatic and cell culture assays for SARS-CoV-2 main protease interaction with ambenonium

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月27日

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  • Juliana Ângelo de Souza,
  • Isabela de Souza Gomes,
  • Luciana de Souza Fernandes,
  • Luis Adan Flores Andrade,
  • Luciana Ângelo de Souza,
  • Vinícius de Almeida Paiva,
  • Sheila Cruz Araujo,
  • Leonardo Henrique Franca de Lima,
  • Roberto Sousa Dias,
  • Raquel Cardoso de Melo-Minardi,
  • Flávio Guimarães da Fonseca,
  • Sérgio Oliveira de Paula,
  • Sabrina de Azevedo Silveira

摘要

The 2019 pandemic of coronavirus disease (COVID-19) caused by SARS-CoV-2 led to millions of deaths worldwide since its emergence. The viral genomic material can code structural and non-structural proteins including the main protease or 3CLpro, a cysteine protease that cleavages the viral polyprotein generating 11 proteins that participate in viral pre-replication. Thus, 3CLpro is a promising therapeutic target for SARS-CoV-2 inhibition by new drugs or drug repositioning because 3CLpro is dissimilar to human proteases. We conducted in vitro assays demonstrating the modulation activity of ambenonium, a drug already used in Myasthenia gravis that acts by inhibiting the action of acetylcholinesterase, and had its potential inhibitory activity against viral replication pointed out in a previous in silico study. In concentrations of 100 µM, 50 µM, 25 µM, 10 µM, and 1 µM there was no inhibition in the formation of lysis plates, with a slight increase in the genome copy number at the higher concentrations evaluated. However, in the concentrations of 0,1 µM and 0,01 µM, there was a reduction in the number of lysis plates. This behavior suggests that the ambenonium acts as a modulator of viral activity in vitro. To investigate potential conformational changes in the protein between dimeric and monomeric forms in the presence of the compound, a local docking analysis was performed. Results indicated this conformational shift is possible, though further studies are needed to confirm these findings.