SARS-CoV-2 exploits cellular RAD51 to promote viral propagation: implication of RAD51 inhibitor as a potential drug candidate against COVID-19

RAD51 is an important factor involved in the homologous recombination and repair of DNA breaks, which has also been implicated in various virus replication processes. We have previously reported that hepatitis C virus (HCV) exploits cellular RAD51 to promote viral propagation. Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is also an RNA virus, we interrogated whether SARS-CoV-2 could coopt RAD51 for its propagation. Here, we showed that silencing of RAD51 impaired SARS-CoV-2 propagation. We further demonstrated that RAD51 colocalized with SARS-CoV-2 RNA in Vero E6 cells. Interestingly, RAD51 interacted with SARS-CoV-2 3CL protease. This suggests that RAD51 inhibitors may block SARS-CoV-2 propagation. Hence, we evaluated multiple RAD51 inhibitors as potential drug candidates for coronavirus disease 2019 (COVID-19). Among these, B02, 4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), IBR2, and RI(dl)-2 significantlydecreased RNA, protein, and infectious virion levels of Wuhan and variants of SARS-CoV-2. Antiviral activity of DIDS was further confirmedin the Syrian hamster model. Molecular docking model showed that these chemicals interfered with RAD51 through dimerization interface. These data suggest that SARS-CoV-2 exploits host RAD51 to facilitate viral propagation, and hence, RAD51 inhibitor may serve as a putative novel therapeutic agent for the treatment of COVID-19.