Cancer Biology, Lerner Research Institute, Cleveland Clinic, 2111 East 96th St, Cleveland, OH 44106, USA.
Laboratorio di Virologia Molecolare, Dipartimento di Scienze della Vita e Dell'Ambiente, Universitá degli Studi di Cagliari, Cittadella Universitaria di Monserrato SS554, 09042 Monserrato, Italy.
Viruses. 2023 Jul 13;15(7):1539. doi: 10.3390/v15071539.
Viral replication often depends on RNA maturation and degradation processes catalyzed by viral ribonucleases, which are therefore candidate targets for antiviral drugs. Here, we synthesized and studied the antiviral properties of a novel nitrocatechol compound () and other analogs that are structurally related to the catechol derivative dynasore. Interestingly, compound strongly inhibited two DEDD box viral ribonucleases, HIV-1 RNase H and SARS-CoV-2 nsp14 3'-to-5' exoribonuclease (ExoN). While inhibited SARS-CoV-2 ExoN activity, it did not interfere with the mRNA methyltransferase activity of nsp14. In silico molecular docking placed compound in the catalytic pocket of the ExoN domain of nsp14. Finally, inhibited SARS-CoV-2 replication but had no toxicity to human lung adenocarcinoma cells. Given its simple chemical synthesis from easily available starting materials, these results suggest that might be a lead compound for the design of new antiviral compounds that target coronavirus nsp14 ExoN and other viral ribonucleases.
病毒复制通常依赖于病毒核糖核酸酶催化的 RNA 成熟和降解过程，因此这些酶是抗病毒药物的候选靶点。在这里，我们合成并研究了一种新型硝基邻苯二酚化合物 () 和其他与邻苯二酚衍生物 dynasore 结构相关的类似物的抗病毒特性。有趣的是，化合物 强烈抑制了两种 DEDD 盒病毒核糖核酸酶，HIV-1 RNase H 和 SARS-CoV-2 nsp14 3'-5'外切核酸酶 (ExoN)。虽然 抑制了 SARS-CoV-2 ExoN 的活性，但它不干扰 nsp14 的 mRNA 甲基转移酶活性。计算机分子对接将化合物 置于 nsp14 的 ExoN 结构域的催化口袋中。最后， 抑制了 SARS-CoV-2 的复制，但对人肺腺癌细胞没有毒性。鉴于它可以从易得的起始原料简单地化学合成，这些结果表明 可能是设计针对冠状病毒 nsp14 ExoN 和其他病毒核糖核酸酶的新型抗病毒化合物的先导化合物。
