Abstract
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.
Highlights
Globalization, environmental changes, population growth, and urbanization make viral diseases (VDs) one of the major causes of morbidity and mortality in the world [1,2]
A co-immunoprecipitation experiment using antibodies against pro-survival Bcl-xL, Bcl-2, or Mcl-1 followed by mass spectrometry showed that several cellular proteins, including Bad, Bax, Bak, UACA, PAWR, FLII, Trim21, IMMT, 14-3-3, EFHD2, DHX9, DDX3, NLRP3, and LRRFIP2, as well as viral factors M1, NS1, HA, and NP were present in the complexes (Figure S2)
These experiments demonstrated that pro-apoptotic Bcl-2 proteins (Bad, Bax, Bak), PRRs (DHX9, DDX3, LRRFIP2), and other factors can be involved in the programmed death of IAV-infected cells
Summary
Globalization, environmental changes, population growth, and urbanization make viral diseases (VDs) one of the major causes of morbidity and mortality in the world [1,2]. Emerging and re-emerging VDs pose a constant threat to public health [3]. 90 antiviral drugs have been approved to treat human immunodeficiency virus (HIV) 1 and 2, hepatitis B and C viruses (HBV and HCV), cytomegalovirus (CMV), herpes simplex virus (HSV) 1 and 2, human papilloma virus (HPV), varicella zoster virus (VZV), vaccinia virus (VACV), Epstein-Barr virus (EBV), respiratory syncytial virus (RSV), or influenza A and B virus (IAV and FLUBV) infections but not other important. There is an urgent need for the development of novel antivirals, including drugs against emerging and re-emerging VDs. Apoptosis is a cellular antiviral process that can be exploited in development of such drugs [5,6]
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