Lipid based delivery vehicles for antivirals against Coronavirus SARS-CoV-2 – continuation

Coronaviruses, such as SARS-CoV-2, are enveloped by a lipid bilayer. Lipids play an essential role during viral infection that involves the fusion of the viral membrane with the host cell. The recent unprecedented viral pandemic of SARS-CoV-2 has shown an alarming need for effective antivirals. The cysteine proteases Mpro and PLpro, key enzymes in the life cycle of coronaviruses, have been shown to be promising pharmacological targets. The antiviral efficacy of 10 newly synthesized and 6 known inhibitors was tested in vitro in VERO-E6 human kidney epithelial cells infected with the SARS-CoV-2 virus under projects of the proposer’s laboratory (J. Enzyme Inhib. Med. Chem, 2024). The low solubility of the drugs is a drawback for their application in human medicine. However, an enhanced inhibitory effect for the drug incorporated into POPC vesicles was observed. The results indicate that a suitable lipid carrier should fulfill two essential attributes: be composed of a fraction of inverted phase-forming lipids; and have a hydrophobic core sufficiently „soft“ to accommodate lipophilic inhibitor molecules. We propose SAXS/WAXS experiments at the BL11-NCD-SWEET beamline on bioactive lipid bilayer systems and inhibitors of viral proteases aimed at exploiting the lipid system for drug delivery. Lipid carriers will be prepared from polyunsaturated PE and PC, enriched with polyunsaturated fatty acids or plasmalogens that have been shown to have antiviral activity.