CGM23 corresponds to a pan-coronavirus lipopeptide inhibitor potently inhibiting virion fusion.

We developed a pan-coronavirus lipopeptide fusion inhibitor, CGM23, which binds to the highly conserved spike heptad repeat-1 domain, thus interrupting the formation of the six-helix bundle required for membrane fusion. In vitro, CGM23 potently inhibited infection by all human coronaviruses tested, including SARS-CoV, MERS-CoV, and SARS-CoV-2 and the seasonal coronaviruses. CGM23 is based on the amino acid sequence of SARS-CoV-2 spike protein. Computational modeling, 4-phenylbutanoic acid was appended to the N-terminus to mimic interactions with the hydrophobic pocket adjacent to the heptad repeat-2. A C-terminal addition of palmitic acid via a PEG linker enhanced CGM23's fusion inhibition. In a wild-type mouse model infected with mouse-adapted SARS-CoV-2, intranasal CGM23 prevented lung infection when given 30 min before challenge. Furthermore, therapeutic CGM23 8 h post-inoculation significantly reduced viral loads in the lungs. In summary, CGM23 represents a promising pan-coronavirus inhibitor with both potential therapeutic and prophylactic activity in humans.