Research Group on Biological and Molecular Chemistry, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceió, 57072-970, Brazil.
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China.
Curr Top Med Chem. 2023;23(17):1625-1639. doi: 10.2174/1568026623666230411095417.
The Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Nowadays, modern society has faced a new challenging problem, the emergence of novel SARS-CoV-2 variants of concern (VOCs). In this context, the Omicron (B.1.1.529) variant, having more than 60 mutations when compared to its ancestral wild-type virus, has infected many individuals around the world. It is rapidly spread person-to-person due to its increased transmissibility. Additionally, it was demonstrated that this newest variant and its subvariants have the capability of evading the host immune system, being resistant to neutralizing antibodies. Moreover, it has been proven to be resistant to monoclonal antibodies and several different vaccines. This ability is associated with a huge number of mutations associated with its spike (S) glycoprotein, which presents at least 15 mutations. These mutations are able to modify the way how this virus interacts with the host angiotensin-converting enzyme 2 (ACE2), increasing its infectivity and making the therapeutic alternatives more ineffective. Concerning its chymotrypsin-like picornavirus 3C-like protease (3CLpro) and RNA-dependent RNA polymerase (RdRp), it has been seen that some compounds can be active against different SARS-CoV-2 variants, in a similar mode than its wild-type precursor. This broad spectrum of action for some drugs could be attributed to the fact that the currently identified mutations found in 3CLpro and RNA proteins being localized near the catalytic binding site, conserving their activities. Herein this review, we provide a great and unprecedented compilation of all identified and/or repurposed compounds/drugs against this threatening variant, Omicron. The main targets for those compounds are the protein-protein interface (PPI) of S protein with ACE2, 3CLpro, RdRp, and Nucleocapsid (N) protein. Some of these studies have presented only in silico data, having a lack of experimental results to prove their findings. However, these should be considered here since other research teams can use their observations to design and investigate new potential agents. Finally, we believe that our review will contribute to several studies that are in progress worldwide, compiling several interesting aspects about VOCs associated with SARS-CoV- 2, as well as describing the results for different chemical classes of compounds that could be promising as prototypes for designing new and more effective antiviral agents.
新型严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2)引起的 2019 年冠状病毒病 (COVID-19) 大流行，已导致数百万人死亡，并威胁着公众健康和安全。如今，现代社会面临着一个新的挑战问题，即新型 SARS-CoV-2 变体关注 (VOCs) 的出现。在这种情况下，与原始野生型病毒相比，奥密克戎 (B.1.1.529) 变体有超过 60 处突变，已感染了世界各地的许多人。由于其传染性增强，它在人与人之间迅速传播。此外，研究表明，这种最新变体及其亚变体能够逃避宿主免疫系统，对中和抗体具有抗性。此外，它被证明对单克隆抗体和几种不同的疫苗具有抗性。这种能力与与它的刺突 (S) 糖蛋白相关的大量突变有关，该糖蛋白至少有 15 处突变。这些突变能够改变该病毒与宿主血管紧张素转换酶 2 (ACE2) 相互作用的方式，从而增加其感染力，并使治疗选择变得更加无效。关于它的糜蛋白酶样小核糖核酸病毒 3C 样蛋白酶 (3CLpro) 和 RNA 依赖性 RNA 聚合酶 (RdRp)，已经看到一些化合物可以以类似于其野生型前体的方式对不同的 SARS-CoV-2 变体有效。对于一些药物来说，这种广谱的作用可能归因于这样一个事实，即目前在 3CLpro 和 RNA 蛋白中发现的突变定位于催化结合位点附近，保留了它们的活性。在本文中，我们提供了一份针对这种威胁性变体奥密克戎的所有已识别和/或重新定位的化合物/药物的前所未有的汇编。这些化合物的主要靶点是 S 蛋白与 ACE2、3CLpro、RdRp 和核衣壳 (N) 蛋白的蛋白-蛋白相互作用 (PPI)。其中一些研究仅提供了计算机数据，缺乏实验结果来证明其发现。然而，这些都应该在这里考虑，因为其他研究团队可以利用他们的观察结果来设计和研究新的潜在试剂。最后，我们相信我们的综述将有助于全世界正在进行的几项研究，汇编了与 SARS-CoV-2 相关的 VOCs 的几个有趣方面，并描述了不同化学类化合物的结果，这些化合物可能作为设计新的更有效的抗病毒药物的原型具有潜力。
