Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2

Abstract

A novel series of peptidomimetic aldehydes was designed and synthesized to target 3C protease (3C^pro) of enterovirus 71 (EV71). Most of the compounds exhibited high antiviral activity, and among them, compound <b>18p</b> demonstrated potent enzyme inhibitory activity and broad-spectrum antiviral activity on a panel of enteroviruses and rhinoviruses. The crystal structure of EV71 3C^pro in complex with <b>18p</b> determined at a resolution of 1.2 Å revealed that <b>18p</b> covalently linked to the catalytic Cys147 with an aldehyde group. In addition, these compounds also exhibited good inhibitory activity against the 3CL^pro and the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially compound <b>18p</b> (IC₅₀ = 0.034 μM, EC₅₀ = 0.29 μM). According to our previous work, these compounds have no reasons for concern regarding acute toxicity. Compared with <b>AG7088</b>, compound <b>18p</b> also exhibited good pharmacokinetic properties and more potent anticoronavirus activity, making it an excellent lead for further development.