Abstract
The search for new active substances against SARS-CoV-2 is still a central challenge
after the COVID-19 pandemic. Antiviral agents to complement vaccination are an important
pillar in the clinical situation. Selected cannabinoids such as cannabigerol, cannabicyclol,
cannabichromene, and cannabicitran from Cannabis sativa and synthetic homologues of cannabigerol and cannabicyclol were evaluated for effects
on the cell viability of Vero cells (CC50 of cannabigerol and cannabicyclol 40 resp. 38 µM) and reduced virus entry of vesicular
stomatitis pseudotyped viruses with surface-expressed SARS-CoV-2 spike protein at
20 µM. In addition to a reduction of pseudotyped virus entry, a titer reduction assay
on Vero cells after preincubation of Wuhan SARS-CoV-2 significantly confirmed antiviral
activity. Investigations on the molecular targets addressed by cannabigerol and cannabicyclol
indicated that both compounds are inhibitors of SARS-CoV-2 spike protein-mediated
membrane fusion, as could be shown by a virus-free reporter fusion inhibition assay
(EC50 for cannabigerol 5.5 µM and for cannabicyclol 10.8 µM) and by monitoring syncytia
formation in Vero reporter cells. Selectivity indices were calculated as 7.4 for cannabigerol
and 3.5 for cannabicyclol. Systematic semisynthetic alterations of cannabigerol and
cannabicyclol indicated that the side chains of both compounds do not contribute to
the observed anti-membrane fusion activity.
Keywords
COVID-19 - SARS-CoV-2 -
Cannabis sativa
- Cannabaceae - cannabinoids - cannabigerol - cannabicyclol - membrane fusion - virulence
factors
