A genetic trap for small molecule inhibitors of the SARS-CoV-2 main protease (En genetisk fälla för småmolekyler som inhiberar SARS-CoV-2 main protease)

The main protease (MPR; 3CL-pro) of SARS-CoV-2 is essential for viral propagation and is a druggable target based on evidence from other viruses. Small molecule inhibitors of the MPR will be screened in vivo, filtering out molecules that do not enter cells and exert their action there. In vivo functional screens are also favorable as there are indications that the MPR active site of SARS-CoV-2 is flexible, making purely structure-based designs difficult.  We will use a highly sensitive double genetic selection system in yeast, based on protease cleavage of a toxin or its antitoxin, engineered to include a protease cleavage site. Cells are tagged with fluorescent markers of different wavelengths and grown in competition, allowing for a quantitative readout. The chemical libraries to be screened are enriched for privileged structures. Screening will be performed in high-throughput format in a laboratory robot capable of reading fluorescence (collaboration with Ross King). Verified hits from the screen will be further developed to antiviral lead molecules in medicinal chemistry (collaboration with Morten Grøtli).   New antiviral inhibitors will curb disease symptoms of severely sick patients. If drug-resistant mutants of SARS-CoV-2 arise in the future, having established this functional selection system gives a lasting resource to screen again for new antiviral molecules. Biokemi och molekylärbiologi; Mikrobiologi; Medicinsk bioteknologi (inriktn. mot cellbiologi (inkl. stamcellsbiologi) molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)