Scientists have identified a small molecule that inhibits multiple different viruses, including SARS-CoV-2, in tissue culture and in mice by targeting the same signaling pathway. By identifying a host cell pathway that a wide variety of viruses rely on for successful infection, the findings suggest a possible target for broad-spectrum antiviral drugs. Novel viruses - including SARS-CoV-2, HIV, Zika virus, and avian influenza A - can present unique challenges for researchers, since interactions between viruses and their hosts often drive evolutionary changes that diversify both the viruses and hosts' responses. To keep ahead of this arms race, scientists have sought evolutionarily conserved mechanisms, common to many host-virus interactions, that can offer sweeping solutions. To investigate whether the TGF-β signaling pathway could serve as a target for antiviral therapies against numerous viruses, Shuofeng Yuan and colleagues performed screens of previously identified inhibitors of the pathway. They found that one such compound, the small molecule N-(p-Amylcinnamoyl)anthranilic acid (or ACA), successfully inhibited influenza A, MERS-CoV, SARS-CoV-2, HIV, adenovirus, and two picornaviruses, both in tissue culture and in mice. They also found that ACA achieved this by blocking the interaction of AP2M1, a subunit of the AP2 adaptor complex that is known to interact with the TGF-β pathway, with an amino acid sequence present in many viral proteins. Blocking this host-virus protein interaction interfered with proper subcellular localization of virus components, thereby inhibiting a productive infection. These findings point to a target and a possible broad-spectrum therapy to treat viral outbreaks, including the current COVID-19 pandemic.