Abstract

Enterovirus infections have become a serious public health threat to young children, leading to hand-foot-and-mouth disease and more severe nervous system diseases . Due to the lack of licensed anti enterovirus drugs , we reported herein that a Tenovin-1 analog, acylthiourea-based 4-( tert -butyl)- N -((4-(4-( tert -butyl)benzamido)phenyl)carbamothioyl) benzamide ( AcTU ), displayed low nanomolar anti-EV-A71 activity with an EC 50 of 1.0 nM in RD cells. Moreover, AcTU exhibited nanomolar to picomolar inhibitory activity against a series of enteroviruses including EV-D68, CV-A21, CV-A16 and CV-B1 (EC 50  = 0.75–17.15 nM). Mechanistic studies indicated that AcTU inhibited enterovirus proliferation by targeting 3D polymerase . In addition, AcTU displayed moderate pharmacokinetic properties in rats (F = 7.4%, T 1/2  = 3.26 h), and in vivo protection studies demonstrated that AcTU orally administered at 0.6 mg/kg/d was highly protective against lethal EV-A71 challenge in mice, potentially reducing mortality from 100% to 20% as well as alleviating symptoms. These results suggested that AcTU could be a potent clinical candidate for the treatment of enterovirus infections.