Discovery of a novel inhibitor of macropinocytosis with antiviral activity

• Published in: Molecular therapy Vol. 32; no. 9; pp. 3012 - 3024
• Main Authors: Porebski, Bartlomiej, Christ, Wanda, Corman, Alba, Haraldsson, Martin, Barz, Myriam, Lidemalm, Louise, Häggblad, Maria, Ilmain, Juliana, Wright, Shane C., Murga, Matilde, Schlegel, Jan, Jarvius, Malin, Lapins, Maris, Sezgin, Erdinc, Bhabha, Gira, Lauschke, Volker M., Carreras-Puigvert, Jordi, Lafarga, Miguel, Klingström, Jonas, Hühn, Daniela, Fernandez-Capetillo, Oscar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2024
• Subjects: antivirals; chemical screen; drug development; macropinocytosis; Medicin och hälsovetenskap; mpox virus; pseudotype virus; SARS-CoV-2; tick-borne encephalitis virus; antivirals; SARS-CoV-2; pseudotype virus; macropinocytosis; mpox virus; drug development; chemical screen; tick-borne encephalitis virus
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2024.06.038

Several viruses hijack various forms of endocytosis in order to infect host cells. Here, we report the discovery of a 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 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 mpox 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 the discovery of a molecule that inhibits macropinocytosis, thereby limiting the infectivity of viruses that use this entry route such as SARS-CoV2. [Display omitted] Porebski and colleagues report on a chemical screen that enables the identification of a new chemical series that inhibits viral infection by several viruses, including SARS-CoV-2. The drug, named virapinib, limits viral infection by inhibiting macropinocytosis, an endocytic route by which multiple viral particles are engulfed by host cells.