Porebski, B.; Christ, W.; Corman, A.; Haraldsson, M.; Barz, M.; Lidemalm, L.; Haggblad, M.; Illmain, J.; Wright, S.; Murga, M.; Schlegel, J.; Sezgin, E.; Bhabha, G.; Lauschke, V. M.; Lafarga, M.; Klingstrom, J.; Huhn, D.; Fernandez-Capetillo, O.

Several viruses hijack various forms of endocytosis in order to infect host cells. Here, we report the discovery of a new molecule with antiviral properties that we named virapinib, which limits viral entry by macropinocytosis. The identification of virapinib derives from a chemical screen using High-Throughput Microscopy, where we identified new chemical entities capable of preventing infection with a pseudotype virus expressing the spike (S) protein from SARS-CoV-2. Subsequent experiments confirmed the capacity of virapinib to inhibit infection by SARS-CoV-2, as well as by additional viruses, such as Monkeypox virus and TBEV. Mechanistic analyses revealed that the compound inhibited macropinocytosis, limiting this entry route for the viruses. Importantly, virapinib has no significant toxicity to host cells. In summary, we present a new molecule that inhibits viral entry via the endocytic route, offering a new alternative to prevent viral infection.