Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio, USA.
J Biomol Struct Dyn. 2024 Feb-Mar;42(4):1733-1750. doi: 10.1080/07391102.2023.2202247. Epub 2023 Apr 28.
COVID-19, the disease responsible for the recent pandemic, is caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The main protease (Mpro) of SARS-CoV-2 is an essential proteolytic enzyme that plays a number of important roles in the replication of the virus in human host cells. Blocking the function of SARS-CoV-2 Mpro offers a promising and targeted, therapeutic option for the treatment of the COVID-19 infection. Such an inhibitory strategy is currently successful in treating COVID-19 under FDA's emergency use authorization, although with limited benefit to the immunocompromised along with an unfortunate number of side effects and drug-drug interactions. Current COVID vaccines protect against severe disease and death but are mostly ineffective toward long COVID which has been seen in 5-36% of patients. SARS-CoV-2 is a rapidly mutating virus and is here to stay endemically. Hence, alternate therapeutics to treat SARS-CoV-2 infections are still needed. Moreover, because of the high degree of conservation of Mpro among different coronaviruses, any newly developed antiviral agents should better prepare us for potential future epidemics or pandemics. In this paper, we first describe the design and computational docking of a library of novel 188 first-generation peptidomimetic protease inhibitors using various electrophilic warheads with aza-peptide epoxides, α-ketoesters, and β-diketones identified as the most effective. Second-generation designs, 192 compounds in total, focused on aza-peptide epoxides with drug-like properties, incorporating dipeptidyl backbones and heterocyclic ring motifs such as proline, indole, and pyrrole groups, yielding 8 hit candidates. These novel and specific inhibitors for SARS-CoV-2 Mpro can ultimately serve as valuable alternate and broad-spectrum antivirals against COVID-19.Communicated by Ramaswamy H. Sarma.
新型严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）引起的 COVID-19 疾病。SARS-CoV-2 的主要蛋白酶（Mpro）是一种重要的蛋白水解酶，在病毒在人宿主细胞中的复制中发挥许多重要作用。阻断 SARS-CoV-2 Mpro 的功能为 COVID-19 感染的治疗提供了一种有前途的靶向治疗选择。这种抑制策略目前在美国食品和药物管理局的紧急使用授权下成功用于治疗 COVID-19，尽管对免疫功能低下者的益处有限，而且存在许多不良反应和药物相互作用。目前的 COVID 疫苗可预防严重疾病和死亡，但对 5-36%的患者出现的长 COVID 基本无效。SARS-CoV-2 是一种快速突变的病毒，将在地方病中持续存在。因此，仍然需要治疗 SARS-CoV-2 感染的替代疗法。此外，由于不同冠状病毒之间 Mpro 的高度保守性，任何新开发的抗病毒药物都应更好地为我们应对潜在的未来疫情或大流行做好准备。在本文中，我们首先描述了使用各种亲电弹头设计和计算对接新型第一代 188 种肽拟肽蛋白酶抑制剂的文库，这些弹头包括氮杂肽环氧化物、α-酮酯和β-二酮，这些被确定为最有效的弹头。第二代设计总共 192 种化合物，重点是具有药物样特性的氮杂肽环氧化物，包含二肽骨架和杂环环模体，如脯氨酸、吲哚和吡咯基团，产生了 8 个候选命中物。这些针对 SARS-CoV-2 Mpro 的新型和特异性抑制剂最终可作为针对 COVID-19 的有价值的替代和广谱抗病毒药物。由 Ramaswamy H. Sarma 交流。
