Neutralizing antibodies and fusion inhibitory peptides
have the
potential required to combat the global pandemic caused by SARS-CoV-2
and its variants. However, the lack of oral bioavailability and enzymatic
susceptibility limited their application, necessitating the development
of novel pan-CoV fusion inhibitors. Herein we report a series of helical
peptidomimetics,d-sulfonyl-γ-AApeptides, which effectively
mimic the key residues of heptad repeat 2 and interact with heptad
repeat 1 in the SARS-CoV-2 S2 subunit, resulting in inhibiting SARS-CoV-2
spike protein-mediated fusion between virus and cell membranes. The
leads also displayed broad-spectrum inhibitory activity against a
panel of other human CoVs and showed strong potencyin vitroandin vivo. Meanwhile, they also demonstrated
complete resistance to proteolytic enzymes or human sera and exhibited
extremely long half-lifein vivoand highly promising
oral bioavailability, delineating their potential as pan-CoV fusion
inhibitors with the potential to combat SARS-CoV-2 and its variants.