Identification of a novel acylthiourea-based potent broad-spectrum inhibitor for enterovirus 3D polymerase in vitro and in vivo

Enterovirus infections have become a serious public health threat to young children, leading to hand-foot-andmouth 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 EC50 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 (EC50 = 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%, T1/2 = 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.

Automated summary

Enterovirus infections pose a serious threat to young children, causing diseases like hand-foot-and-mouth disease and severe nervous system diseases. A new compound called AcTU has shown potential as an effective treatment for enterovirus infections, displaying low nanomolar activity against EV-A71 as well as other enteroviruses. Mechanistic studies have revealed that AcTU inhibits the proliferation of enteroviruses by targeting 3D polymerase. In animal tests, AcTU has demonstrated high protection rates and reduction in symptoms, making it a promising clinical candidate.