Small Molecule Targeting of Atypical p38 Protects Against Viral Infection

Developing therapeutics that target the host kinome is a promising strategy to support current treatments for viral infections. While multiple direct-acting antivirals (DAAs) potentially clear Hepatitis C virus (HCV) infection in most individuals, ~2.4 million individuals are unresponsive to the current DAAs or have secondary infections/complications that impact their treatment potential. Recent studies have demonstrated that atypical p38 activity is crucial for HCV replication and may have broader implications in regulating other viruses. Despite the multifaceted roles of p38 in regulating viral pathogenesis, the molecular mechanisms that underlie atypical p38 activation by viruses remain a critical gap in our understanding of viral physiology. Here, we characterized two atypical p38 allosteric modulators (NC compounds) during HCV infection. We compared the effects of these compounds to current DAAs for HCV and Herpesvirus, respectively. Our data show that treatment of either NC compound rapidly attenuates HCV-induced p38 activation, blocking HCV protein expression and HCV RNA replication. Interestingly, while both NC compounds can successfully attenuate HCV infection, we also found that they displayed the capacity to inhibit the betaherpesvirus, Human Cytomegalovirus (HCMV), and the alpha herpesvirus, Herpes Simplex Virus-1 (HSV-1). Our study is the first to assess the potential of atypical p38 selective modulators to block viral replication. While the current examples are likely not clinically viable, the concept represents an exciting opportunity to support or complement current treatment strategies, shedding light on the importance that host factors play during viral physiology.