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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.