Direct-acting antivirals and host-targeting strategies to combat enterovirus infections

Abstract

Enteroviruses (e.g., poliovirus, enterovirus-A71, coxsackievirus, enterovirus-D68, rhinovirus) include many human pathogens causative of various mild and more severe diseases, especially in young children. Unfortunately, antiviral drugs to treat enterovirus infections have not been approved yet. Over the past decades, several direct-acting inhibitors have been developed, including capsid binders, which block virus entry, and inhibitors of viral enzymes required for genome replication. Capsid binders and protease inhibitors have been clinically evaluated, but failed due to limited efficacy or toxicity issues. As an alternative approach, host-targeting inhibitors with potential broad-spectrum activity have been identified. Furthermore, drug repurposing screens have recently uncovered promising new inhibitors with disparate viral and host targets. Together, these findings raise hope for the development of (broad-range) anti-enteroviral drugs.

ACBD3 is an essential pan-enterovirus host factor that mediates the interaction between viral 3A protein and cellular protein PI4KB

“…PI4KB is recruited by 3A to ROs during enterovirus replication (8, 9), and depletion of PI4KB by RNAi (9) or pharmacologic inhibition (reviewed in (26)) have been shown to suppress virus replication. Enterovirus mutants resistant to inhibitors of PI4KB contain single amino acid substitutions in the 3A protein (e.g., H57Y for CVB3).…”

Management strategies of enterovirus D68 outbreaks: current perspectives

“…53,54 Several direct-acting EV inhibitors have been developed, including capsid binders and inhibitors of viral enzymes required for genome replication such as protease inhibitors, 3D pol inhibitors, and 2C ATPase inhibitors. 55 So far, none have been approved for clinical use. The most widely studied compounds are capsid binders, of which pleconaril, vapendavir, and pocavir are undergoing clinical trials.…”

“…The most widely studied compounds are capsid binders, of which pleconaril, vapendavir, and pocavir are undergoing clinical trials. 55 However, a disadvantage of capsid binders is the emergence of resistant EV-D68 variants, which complicates their clinical use. 56,57 Protease inhibitors may be more promising as direct-acting antiviral drugs, particularly since these often have broadspectrum anti-enteroviral effects.…”

“…Nevertheless, several rupintrivir derivatives are under development as well as preclinical studies of nonpeptidomimetic small molecule inhibitors with a better bioavailability than rupintrivir. 55,56 3D pol inhibitors such as ribavirin have shown promising results for some viruses; however, few have yet been developed against EV. 55 While several 2C ATPase inhibitors have been identified, their effect against EV remains to be tested in clinical trials.…”

“…55,56 3D pol inhibitors such as ribavirin have shown promising results for some viruses; however, few have yet been developed against EV. 55 While several 2C ATPase inhibitors have been identified, their effect against EV remains to be tested in clinical trials. Drug repurposing studies of 2C ATPase inhibitors identified fluoxetine (ie, Prozac ® ) as a potential drug for EV, and it was shown to reduce EV-D68 growth in vitro.…”