FNDR-11124, a broad-spectrum small molecule inhibitor of viral RNA polymerase, restricts replication of SARS-CoV-2 and Influenza virus in vitro and in vivo

The increasing incidence of emerging and re-emerging viral infections is a significant global public health concern, highlighting the importance of developing effective, broad-spectrum antivirals. Direct-acting antivirals targeting viral polymerases are promising therapeutic agents. In the present study, we report the broad-spectrum in vitro antiviral activity of a novel small molecule, termed FNDR-11124, against SARS-CoV-2, Influenza, Kyasanur forest disease virus, as well as representative flaviviruses and alphaviruses. The structure-activity relationship guided chemical modifications demonstrated that the chromone core with mono-hydroxy substitutions is required for the broad-spectrum antiviral activity of FNDR-11124. Mechanism of action studies showed that FNDR-11124 inhibits viral RNA polymerases belonging to different families of viruses. Corroboratively, computational studies indicated binding of FNDR-11124 to the catalytic active site of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and Influenza A. Furthermore, in vivo evaluation against SARS-CoV-2 and Influenza A showed promising antiviral efficacy in animal models of infection. Collectively, these findings suggest that FNDR-11124 represents a novel, direct-acting, broad-spectrum small molecule polymerase inhibitor against viruses of pandemic potential, such as SARS-CoV-2 and Influenza.