Repurposing screen highlights broad-spectrum coronavirus antivirals and their host targets

Haid, Sibylle; Matthaei, Alina; Winkler, Melina; Sake, Svenja M.; Gunesch, Antonia P.; Rückert, Jessica; Vieyres, Gabrielle; Kühl, David; Nguyen, Tu-Trinh; Lasswitz, Lisa; Zapatero, Francisco; Brogden, Graham; Gerold, Gisa; Wiegmann, Bettina; Bilitewski, Ursula; Brönstrup, Mark; Schulz, Thomas F.; Pietschmann, Thomas

Libraries composed of licensed drugs represent a vast repertoire of molecules modulating physiologic processes in humans, thus providing unique opportunities for discovery of host targeting antivirals. We interrogated the ReFRAME repurposing library with 12,993 molecules for broad-spectrum coronavirus antivirals and discovered 134 compounds inhibiting an alphacoronavirus, mapping to 59 molecular target categories. Dominant targets included the 5-hydroxytryptamine receptor and dopamine receptor and cyclin-dependent kinase inhibitors. Counter-screening with SARS-CoV-2 and validation in primary cells identified Phortress, an aryl hydrocarbon receptor (AHR) ligand, Bardoxolone and Omaveloxolone, two nuclear factor, erythroid 2 like 2 (NFE2L2) activators as inhibitors of both alpha- and betacoronaviruses. The landscape of coronavirus targeting molecules provides important information for the development of broad-spectrum antivirals reinforcing pandemic preparedness.