Development of a novel broad-spectrum inhibitor of non-polio enteroviruses associated with acute flaccid myelitis Summary: Despite the eradication of poliovirus in the US and Europe more than 20 years ago, the number of cases of childhood paralysis associated with acute flaccid myelitis (AFM) has been increasing since 2014. This surge correlates with a rise in the number of diagnosed infections of 3 non-polio enteroviruses (NPEVs): enteroviruses D-68 (EV-D68), A71 (EV-A71) and Coxsackievirus A16 (CV-A16) in children. These 3 viruses are associated with a variety of clinical manifestations, including non-specific febrile illness, respiratory manifestations, hand-foot-and-mouth disease (HFMD), encephalitis and paralysis (AFM). NPEVs cause more than 10 million infections worldwide resulting in thousands of hospital admissions, missed days of work and school every year in the US alone. Consequently, these infections have significant medical, social and economic impact. Apart from 2 vaccines marketed locally in China for EV-A71, no approved vaccines or therapeutics exist to treat or prevent NPEV infections or the development of AFM. We discovered a novel series of compounds that exhibit selective potent antiviral activity against a group of enteroviruses (poliovirus, EV-D68 and EV-A71) and several other RNA virus families, but not DNA viruses. Selection for resistant mutants, focused on enteroviruses, identified 2 amino acid substitutions within the RNA dependent RNA polymerase of poliovirus that conferred resistance. Our hypothesis is that these compounds constitute a novel series of RNA polymerase inhibitors. The main objective of this program is to develop a safe and efficacious broad-spectrum antiviral small molecule inhibitor of all 3 NPEVs that have been linked to AFM: EV-D68, EV-A71 and CV-A16.
This project is designed to develop small-molecule broad-spectrum inhibitors of non-polio enteroviruses associated with acute flaccid myelitis. The starting series of small molecules demonstrated low cytotoxicity profile and broad-spectrum antiviral activity against a group of enteroviruses (poliovirus, EV-D68 and EV-A71) and several other RNA virus families, but not DNA viruses. The proposed work will seek to optimize the potency, selectivity and drug-like properties of these novel compounds. It will also establish activity in mouse brain slice cultures and suitable tolerability and PK profiles in mice.
