Antiviral Activity of Cannabidiolic Acid and Its Methyl Ester against SARS-CoV-2

Inthe present study, the antiviral activity of cannabinoids isolatedfrom Cannabis sativa L. was assessed in vitro against a panel of SARS-CoV-2 variants, indicating cannabidiolicacid (CBDA) was the most active. To overcome the instability issueof CBDA, its methyl ester was synthesized and tested for the firsttime for its antiviral activity. CBDA methyl ester showed a neutralizingeffect on all the SARS-CoV-2 variants tested with greater activitythan the parent compound. Its stability in vitro wasconfirmed by ultra-high-performance liquid chromatography (UHPLC)analysis coupled with high-resolution mass spectrometry (HRMS). Inaddition, the capacity of both CBDA and its derivative to interactwith the virus spike protein was assessed in silico. These results showed that CBDA methyl ester can be considered asa lead compound to be further developed as a new effective drug againstCOVID-19 infection.