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Inhibitors of Anti-apoptotic Bcl-2 Family Proteins Exhibit Potent and Broad-Spectrum Anti-mammarenavirus Activity via Cell Cycle Arrest at G0/G1 Phase.
Kim, Yu-Jin; Witwit, Haydar; Cubitt, Beatrice; de la Torre, Juan C.
  • Kim YJ; Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, California, USA.
  • Witwit H; Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, California, USA.
  • Cubitt B; Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, California, USA.
  • de la Torre JC; Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, California, USA.
J Virol ; 95(24): e0139921, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1691426
ABSTRACT
Targeting host factors is a promising strategy to develop broad-spectrum antiviral drugs. Drugs targeting anti-apoptotic Bcl-2 family proteins that were originally developed as tumor suppressors have been reported to inhibit multiplication of different types of viruses. However, the mechanisms whereby Bcl-2 inhibitors exert their antiviral activity remain poorly understood. In this study, we have investigated the mechanisms by which obatoclax (OLX) and ABT-737 Bcl-2 inhibitors exhibited a potent antiviral activity against the mammarenavirus lymphocytic choriomeningitis virus (LCMV). OLX and ABT-737 potent anti-LCMV activity was not associated with their proapoptotic properties but rather with their ability to induce cell arrest at the G0/G1 phase. OLX- and ABT-737-mediated inhibition of Bcl-2 correlated with reduced expression levels of thymidine kinase 1 (TK1), cyclin A2 (CCNA2), and cyclin B1 (CCNB1) cell cycle regulators. In addition, small interfering RNA (siRNA)-mediated knockdown of TK1, CCNA2, and CCNB1 resulted in reduced levels of LCMV multiplication. The antiviral activity exerted by Bcl-2 inhibitors correlated with reduced levels of viral RNA synthesis at early times of infection. Importantly, ABT-737 exhibited moderate efficacy in a mouse model of LCMV infection, and Bcl-2 inhibitors displayed broad-spectrum antiviral activities against different mammarenaviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results suggest that Bcl-2 inhibitors, actively being explored as anticancer therapeutics, might be repositioned as broad-spectrum antivirals. IMPORTANCE Antiapoptotic Bcl-2 inhibitors have been shown to exert potent antiviral activities against various types of viruses via mechanisms that are currently poorly understood. This study has revealed that Bcl-2 inhibitors' mediation of cell cycle arrest at the G0/G1 phase, rather than their proapoptotic activity, plays a critical role in blocking mammarenavirus multiplication in cultured cells. In addition, we show that Bcl-2 inhibitor ABT-737 exhibited moderate antimammarenavirus activity in vivo and that Bcl-2 inhibitors displayed broad-spectrum antiviral activities against different mammarenaviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results suggest that Bcl-2 inhibitors, actively being explored as anticancer therapeutics, might be repositioned as broad-spectrum antivirals.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Arenaviridae / Apoptosis / Proto-Oncogene Proteins c-bcl-2 / COVID-19 Drug Treatment Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: J Virol Year: 2021 Document Type: Article Affiliation country: Jvi.01399-21

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Arenaviridae / Apoptosis / Proto-Oncogene Proteins c-bcl-2 / COVID-19 Drug Treatment Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: J Virol Year: 2021 Document Type: Article Affiliation country: Jvi.01399-21