Glycosylated 18β-glycyrrhetinic acid derivatives as promising inhibitors of the SARS-CoV-2 main protease.

The SARS-CoV-2 main protease (M) is a validated antiviral target for COVID-19 therapeutics due to its essential role in viral replication and absence of human homologs. Here, we report the synthesis and characterization of glycosylated 18β-glycyrrhetinic acid (18β-GA) derivatives using a one-pot, four-enzyme system to improve drug-like properties and antiviral efficacy. Among the derivatives, 18β-GA-3--β-Glc and 18β-GA-30--β-Glc exhibited promising M inhibition, with IC values of 8.70 ± 0.80 μM and 4.77 ± 0.49 μM, respectively. Biolayer interferometry revealed favorable binding affinities and reversible interactions with M, while molecular docking demonstrated their stable binding conformations resembling that of GC376. These glycosides also showed improved predicted oral bioavailability and physicochemical profiles. Our findings support the potential of glycosylated 18β-GA derivatives as cost-effective and scalable antiviral candidates targeting SARS-CoV-2 M.