{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T17:18:20Z","timestamp":1768497500001,"version":"3.49.0"},"posted":{"date-parts":[[2021,8,17]]},"group-title":"Microbiology","reference-count":46,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2021,8,17]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>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 pro-apoptotic properties, but rather their ability of inducing cell arrest at 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, siRNA-mediated knock down 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 SARS-CoV-2. Our results suggest that Bcl-2 inhibitors, actively being explored as anti-cancer therapeutics, might be repositioned as broad-spectrum antivirals.<\/jats:p>\n                <jats:sec>\n                  <jats:title>IMPORTANCE<\/jats:title>\n                  <jats:p>\n                    Anti-apoptotic 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 mediated cell cycle arrest at the G0\/G1 phase, rather than their pro-apoptotic activity, plays a critical role in blocking mammarenavirus multiplication in cultured cells. In addition, we show that Bcl-2 inhibitor ABT-737 exhibited moderate anti-mammarenavirus activity\n                    <jats:italic>in vivo<\/jats:italic>\n                    , and that Bcl-2 inhibitors displayed broad-spectrum antiviral activities against different mammarenaviruses and SARS-CoV-2. Our results suggest that Bcl-2 inhibitors, actively being explored as anti-cancer therapeutics, might be repositioned as broad-spectrum antivirals.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2021.08.16.456587","type":"posted-content","created":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T16:10:53Z","timestamp":1629216653000},"source":"Crossref","is-referenced-by-count":3,"title":["Inhibitors of anti-apoptotic Bcl-2 family proteins exhibit potent and broad-spectrum anti-mammarenavirus activity via cell cycle arrest at G0\/G1 phase"],"prefix":"10.64898","author":[{"given":"Yu-Jin","family":"Kim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haydar","family":"Witwit","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatrice","family":"Cubitt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan C.","family":"de la Torre","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2021081908400608000_2021.08.16.456587v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2017.186"},{"key":"2021081908400608000_2021.08.16.456587v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2952"},{"key":"2021081908400608000_2021.08.16.456587v1.3","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a008656"},{"key":"2021081908400608000_2021.08.16.456587v1.4","doi-asserted-by":"crossref","unstructured":"Campbell KJ , Tait SWG . 2018. Targeting BCL-2 regulated apoptosis in cancer. Open Biol 8.","DOI":"10.1098\/rsob.180002"},{"key":"2021081908400608000_2021.08.16.456587v1.5","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-16-0031"},{"key":"2021081908400608000_2021.08.16.456587v1.6","doi-asserted-by":"crossref","unstructured":"Bulanova D , Ianevski A , Bugai A , Akimov Y , Kuivanen S , Paavilainen H , Kakkola L , Nandania J , Turunen L , Ohman T , Ala-Hongisto H , Pesonen HM , Kuisma MS , Honkimaa A , Walton EL , Oksenych V , Lorey MB , Guschin D , Shim J , Kim J , Than TT , Chang SY , Hukkanen V , Kulesskiy E , Marjomaki VS , Julkunen I , Nyman TA , Matikainen S , Saarela JS , Sane F , Hober D , Gabriel G , De Brabander JK , Martikainen M , Windisch MP , Min JY , Bruzzone R , Aittokallio T , Vaha-Koskela M , Vapalahti O , Pulk A , Velagapudi V , Kainov DE . 2017. Antiviral Properties of Chemical Inhibitors of Cellular Anti-Apoptotic Bcl-2 Proteins. 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