Development of 2C inhibitors as broad-spectrum enterovirus antivirals

Project Summary Non-polio enteroviruses (NPEVs) are etiological agents for several human diseases including respiratory infections, hand-foot-and-mouth disease (HFMD), aseptic meningitis, encephalitis, neonatal sepsis, myocarditis, conjunctivitis, and acute flaccid paralysis. Among the more than 100 serotypes of NPEVs, some of the most significant pathogens are enterovirus D68 (EV-D68), enterovirus A71 (EV-A71) and coxsackievirus B3 (CV-B3). According to CDC, these NPEVs combined have caused 10 to 15 million infections and tens of thousands of hospitalizations in the U.S. Clearly, NPEVs are a public concern for both U.S. and the world. No vaccines are available in the U.S. for the NPEVs such as EV-D68, EV-A71, and CV-B3. Three inactivated EV-A71 vaccines are available in China. However, there are not broadly protective, and the efficacy is limited to certain strains. There is no FDA-approved antiviral for any of these NPEVs. Thus, there is a pressing need to develop orally bioavailable pan-enterovirus antivirals. This proposal focuses on targeting the enterovirus nonstructural 2C protein for the development of orally bioavailable broad-spectrum NPEV antivirals. Specifically, in Aim 1, we will optimize the antiviral activity and pharmacokinetic properties of three series of 2C inhibitors. In Aim 2, we will determine the high-resolution X- ray crystal structures of EV-A71, EV-D68, and CV-B3 2C proteins with structurally disparate 2C inhibitors. In Aim 3, we will evaluate the in vivo antiviral efficacy of 2C inhibitors in EV-D68 and EV-A71 infection mouse models. Successful implementation of this proposal will provide orally bioavailable broad-spectrum NPEV drug candidates for further development.