Targeted Drug Cocktail Reduces Enterovirus Replication

Enteroviruses infect multiple human tissues and cause diseases including meningitis, the common cold, myocarditis, pancreatitis, hepatitis, poliomyelitis, sepsis, type 1 diabetes, hand, foot, and mouth disease. Despite this burden, no antiviral therapy has been approved to date. Progress has been limited by the structural and topical diversity of enteroviruses because many variants are intrinsically insensitive to candidate agents and sensitive strains develop resistance rapidly. Here, we report that the approved anticancer drug vemurafenib inhibited replication of some tested enteroviruses in cell cultures. Passage of echovirus EV1 for six cycles in cell culture yielded vemurafenib-resistant virus harboring missense mutations in the viral 3A and VP1 proteins, underscoring the need for combination therapy. We therefore evaluated cocktails, combining vemurafenib with the VP1 inhibitor pleconaril and the 3C protease inhibitor AG7404. In cell culture, the cocktails suppressed replication of all seven tested enteroviruses. In infected mice, the triple regimen reduced viral titers in the pancreas. The combination was also effective in human pancreatic, retinal, and brain organoids. These findings support multi-stage targeting of the enterovirus life cycle as a promising path toward broadly active therapeutic cocktails.