Antiviral Properties of Chemical Inhibitors of Cellular Anti-Apoptotic Bcl-2 Proteins

Bulanova, Daria; Ianevski, Aleksandr; Bugai, Andrii; Akimov, Yevhen; Kuivanen, Suvi; Paavilainen, Henrik; Kakkola, Laura; Nandania, Jatin; Turunen, Laura; Ohman, Tiina; Ala-Hongisto, Hanna; Pesonen, Hanna M.; Kuisma, Marika S.; Honkimaa, Anni; Walton, Emma L.; Oksenych, Valentyn; Lorey, Martina B.; Guschin, Dmitry; Shim, Jungmin; Kim, Jinhee; Than, Thoa T.; Chang, So Young; Hukkanen, Veijo; Kulesskiy, Evgeny; Marjomaki, Varpu S.; Julkunen, Ilkka; Nyman, Tuula A.; Matikainen, Sampsa; Saarela, Jani S.; Sane, Famara; Hober, Didier; Gabriel, Gülsah; De Brabander, Jef K.; Martikainen, Miika; Windisch, Marc P.; Min, Ji-Young; Bruzzone, Roberto; Aittokallio, Tero; Vähä-Koskela, Markus; Vapalahti, Olli; Pulk, Arto; Velagapudi, Vidya; Kainov, Denis E.

Viral diseases remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral diseases, new treatments are urgently needed. Here we show that small-molecules, which inhibit cellular anti-apoptotic Bcl-2 proteins (Bcl-2i), induced the premature death of cells infected with different RNA or DNA viruses, whereas, at the same concentrations, no toxicity was observed in mock-infected cells. Moreover, these compounds limited viral replication and spread. Surprisingly, Bcl-2i also induced the premature apoptosis of cells transfected with viral RNA or plasmid DNA but not of mock-transfected cells. These results suggest that Bcl-2i sensitizes cells containing foreign RNA or DNA to apoptosis. A comparison of the toxicity, antiviral activity, and side effects of six Bcl-2i allowed us to select A-1155463 as an antiviral lead candidate. Thus, our results pave the way for the further development of Bcl-2i for the prevention and treatment of viral diseases.