The main protease (M) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent M inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent M inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent M inhibitors with desirable properties have been developed based on available crystal structures of M. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent M inhibitors are also discussed.

中文翻译：

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开发非共价 SARS-CoV-2 Mpro 抑制剂的药物化学策略


SARS-CoV-2 的主要蛋白酶 (M) 因其高度保守性和在病毒生命周期中的重要作用而成为抗 COVID-19 治疗中有吸引力的靶标。共价 M 抑制剂 nirmatrelvir（与药代动力学增强剂利托那韦组合）和非共价抑制剂 enitrelvir 已在临床试验中显示出疗效，并已被批准用于治疗用途。对抗这种流行病需要有效的抗病毒药物，而非共价 M 抑制剂由于其高选择性和良好的成药性可能成为有前途的替代品。基于现有的 M 晶体结构，开发了许多具有理想特性的非共价 M 抑制剂。在本文中，我们描述了用于发现和优化非共价 M 抑制剂的药物化学策略，随后进行了总体概述和批判性分析的可用信息。还讨论了对当前非共价 M 抑制剂开发策略的前瞻性观点和见解。