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

A novel series of peptidomimetic
aldehydes was designed and synthesized
to target 3C protease (3Cpro) of enterovirus 71 (EV71).
Most of the compounds exhibited high antiviral activity, and among
them, compound 18p demonstrated potent enzyme inhibitory
activity and broad-spectrum antiviral activity on a panel of enteroviruses
and rhinoviruses. The crystal structure of EV71 3Cpro in
complex with 18p determined at a resolution of 1.2 Å
revealed that 18p covalently linked to the catalytic
Cys147 with an aldehyde group. In addition, these compounds also exhibited
good inhibitory activity against the 3CLpro and the replication
of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially
compound 18p (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 AG7088, compound 18p also exhibited
good pharmacokinetic properties and more potent anticoronavirus activity,
making it an excellent lead for further development.