Recently, Dai W et al. published a study on Science, 1 in which the two lead compounds 11a and 11b were designed and synthesized based on the features of a key enzyme M pro of SARS-CoV-2 (Fig. 1).In particular, compound 11a is a potential drug candidate for coronavirus disease 2019 (COVID-19) with strong anti-SARS-CoV-2 infection activity, good pharmacokinetics characteristics, and low toxicity.Since December 2019, the outbreak of COVID-19 caused by SARS-CoV-2 2 has caused a serious global public health emergency.So far, the global epidemic is still in the outbreak stage, and the number of new confirmed cases every day has exceeded 100,000 for several days.At present, the main drugs used clinically include interferon-alpha, lopinavir/ritonavir, ribavirin, arbidol, etc.However, these drugs are facing huge controversy due to the large side effects or the lack of clinical verifications of the therapeutic effects. 3Therefore, clarifying the origin and pathogenesis of pneumonia and decoding the key targets against SARS-CoV-2 are the cornerstone to design and discover safe and effective antivirus drugs.Previously, the crystal structure of the M pro protein of SARS-CoV-2 was resolved in complex with an effective inhibitor N3, which was completed by the same group, laying an important foundation for this research. 4M pro plays an irreplaceable role in the life cycle of the virus in the light of it could release a series of functional peptides by hydrolyzing the two proteins necessary for replication and transcription, pp1a and pp1ab. 5Notably, conservatism in coronavirus and lack of homolog in human also enhance the application of M pro in antiviral drug design. 5 The active sites of M pro , which usually include S1', S1, S2, and S4, are highly conserved in all coronaviruses.Accordingly, the rational design can be applied in the discovery of novel SARS-COV-2 inhibitors.Because SARS-CoV M pro inhibitors usually have (S)-γlactam ring to occupy the S1 site, (S)-γ-lactam ring is introduced to interact with the S1 site.Furthermore, an aldehyde group is selected to form a covalent bond with the thiol of the Cys145 residue.The S2 region is capable to accommodate a large group, so a cyclohexyl or 3-fluorophenyl group with large spatial volume is introduced at the corresponding position.Afterwards, an indole group is placed in the S4 region to form intermolecular hydrogen bonds so as to improve drug-like properties.Finally, a synthetic route is developed to afford the lead compounds 11a and 11b.Next, activity, pharmacokinetics properties and toxicity of 11a and 11b were evaluated.In a fluorescence resonance energy transfer (FRET)-based cleavage assay, both compounds 11a and