Design, Synthesis, and Evaluation of Novel Enterovirus 71 Inhibitors as Therapeutic Drug Leads for the Treatment of Human Hand, Foot, and Mouth Disease

Human
hand, foot, and mouth disease (HFMD) is a serious public
health threat with high infection rates in children and infants who
reside in Asia and the Pacific regions, and no effective drugs are
currently available. Enterovirus 71 (EV71) and coxsackievirus A16
are the major etiological pathogens. Based on an essential hydrophobic
pocket on the viral capsid protein VP1, we designed and synthesized
a series of small molecular weight compounds as inhibitors of EV71.
A potential drug candidate named NLD-22 exhibited excellent
antiviral activity (with an EC50 of 5.056 nM and a 100%
protection rate for mice at a dose of 20 mg/kg) and low toxicity. NLD-22 had a favorable pharmacokinetic profile. High-resolution
cryo-electron microscopy structural analysis confirmed NLD-22 bound to the hydrophobic pocket in VP1 to block viral infection.
In general, NLD-22 was indicated to be a promising potential
drug candidate for the treatment of HFMD.