Laboratório de Química Medicinal, Faculdade de Farmácia, Universidade Federal Fluminense, Niterói, RJ, 24241-000, Brazil.
Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-853, Brazil.
Sci Rep. 2024 Apr 18;14(1):8991. doi: 10.1038/s41598-024-59442-4.
COVID-19 is a multisystemic disease caused by the SARS-CoV-2 airborne virus, a member of the Coronaviridae family. It has a positive sense single-stranded RNA genome and encodes two non-structural proteins through viral cysteine-proteases processing. Blocking this step is crucial to control virus replication. In this work, we reported the synthesis of 23 statine-based peptidomimetics to determine their ability to inhibit the main protease (Mpro) activity of SARS-CoV-2. Among the 23 peptidomimetics, 15 compounds effectively inhibited Mpro activity by 50% or more, while three compounds (7d, 8e, and 9g) exhibited maximum inhibition above 70% and IC < 1 µM. Compounds 7d, 8e, and 9g inhibited roughly 80% of SARS-CoV-2 replication and proved no cytotoxicity. Molecular docking simulations show putative hydrogen bond and hydrophobic interactions between specific amino acids and these inhibitors. Molecular dynamics simulations further confirmed the stability and persisting interactions in Mpro's subsites, exhibiting favorable free energy binding (ΔG) values. These findings suggest the statine-based peptidomimetics as potential therapeutic agents against SARS-CoV-2 by targeting Mpro.
COVID-19 是一种由 SARS-CoV-2 空气传播病毒引起的多系统疾病，该病毒属于冠状病毒科。它具有正链单链 RNA 基因组，并通过病毒半胱氨酸蛋白酶加工编码两种非结构蛋白。阻断这一步骤对于控制病毒复制至关重要。在这项工作中，我们报告了 23 种基于合成的合成肽拟肽的合成，以确定它们抑制 SARS-CoV-2 主要蛋白酶（Mpro）活性的能力。在 23 种肽拟肽中，有 15 种化合物有效抑制 Mpro 活性超过 50%，而有 3 种化合物（7d、8e 和 9g）的最大抑制率超过 70%，IC < 1 µM。化合物 7d、8e 和 9g 抑制了约 80%的 SARS-CoV-2 复制，且没有细胞毒性。分子对接模拟显示特定氨基酸与这些抑制剂之间存在氢键和疏水相互作用。分子动力学模拟进一步证实了 Mpro 亚位点中稳定且持久的相互作用，表现出有利的自由能结合（ΔG）值。这些发现表明基于合成的肽拟肽可通过靶向 Mpro 成为针对 SARS-CoV-2 的潜在治疗剂。
