Potent Inhibition of Human Betacoronaviruses by a Short Double-Stapled Peptide Mimicking the HR2 Core Region in Viral Spike Protein

A small hexameric coiled-coil fusion complex formed by
the interaction
between α-helical motif of heptad repeat 2 (HR2core) and HR1 core site (HR1core) in human betacoronavirus
spike protein plays a crucial role in facilitating membrane fusion.
Formation of the six-helix bundle involves the evolutionary conservation
of key residues in the HR1core region. Therefore, to recapitulate
the native conformation of the HR2core peptide α-helix
and the HR1core site conserved residues, we employed hydrocarbon
double-stapling. The resulting all-hydrocarbon stapled peptide M2PA
shows highly potent and broad-spectrum antiviral activity against
SARS-CoV-2 and its emerging variants, as well as other betacoronaviruses
tested. Also, M2PA is effective against authentic SARS-CoV-2 infection
in vivo, and it possesses outstanding pharmacokinetic properties.
This represents the first successful minimization of a pan-coronavirus
inhibitor to an HR2core-based α-helical peptide,
and as such, M2PA peptide stands as a promising candidate for drug
development to combat coronavirus pandemics.