New Phenolic Lipids from the Leaves of Inhibit SARS-CoV-2 Entry into Host Cells.

Induced by the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the COVID-19 pandemic underlined the clear need for antivirals against coronaviruses. In an effort to identify new inhibitors of SARS-CoV-2, a screening of 824 extracts prepared from various parts of 400 plant species belonging to the Rutaceae and Annonaceae families was conducted using a cell-based HCoV-229E inhibition assay. Due to its significant activity, the ethyl acetate extract of the leaves of was selected for further chemical and biological investigations. Mass spectrometry-guided fractionation afforded three undescribed phenolic lipids (-), whose structures were determined via spectroscopic analysis. The absolute configurations of and were determined by analyzing Mosher ester derivatives. The antiviral activity against SARS-CoV-2 was subsequently shown, with IC values of 0.20 and 0.05 µM for and , respectively. The mechanism of action was further assessed, showing that both and are inhibitors of coronavirus entry by acting directly on the viral particle. Phenolic lipids from might be a source of new antiviral agents against human coronaviruses.