Development of Orally Bioavailable Octahydroindole-Based Peptidomimetic Derivative as a Broad-Spectrum Inhibitor against HCoV-OC43 and SARS-CoV‑2

A series
of novel Mpro inhibitors was designed
and synthesized
to combat the coronavirus, such as HCoV-OC43 and SARS-CoV-2, and several
compounds showed comparable antiviral activity to nirmatrelvir. Among
them, an octahydroindole-based peptidomimetic covalent inhibitor 28f showed strong inhibitory activity against Mpros and exhibited broad-spectrum anticoronavirus activity with EC50 values ranging from 0.027 to 4.41 μM. Besides, this
compound displayed potent antiviral activity against EV71. Compared
to FB2001, 28f displayed better pharmacokinetic
properties, and the value of oral bioavailability in CD-1 mice and
Beagle dogs was improved to 10.4 and 10.2%, respectively. In addition,
oral treatment with 28f could significantly reduce the
viral loads of HCoV-OC43 in mice, and compound 28f could
also effectively reduce lung viral loads in a K18-hACE2 transgenic
mouse model without ritonavir. Taken together, compound 28f is a promising orally bioavailable broad-spectrum antiviral drug
candidate that deserves further research.