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.

Figure 1

Enterovirus genome, replication cycle, and antiviral targets. (a) The enterovirus genome encodes four structural proteins (VP1-VP4) and seven non-structural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D). IRES: internal ribosome entry site. (b) The enterovirus life cycle begins with the attachment of the virus particle to a cellular receptor followed by the internalization of the particle into the host cell. The genome is released and directly translated into a polyprotein, which is processed by virally encoded proteases into the individual viral proteins. Non-structural proteins rewire host cell membranes and generate replication organelles (ROs) for viral RNA replication. Several host proteins, such as PI4KB (phosphatidylinositol 4-kinase III beta) and OSBP (oxysterol-binding protein), are recruited to ROs by viral 3A protein, which results in ROs with a unique lipid composition. Genome replication starts with synthesis of complementary negative-stranded RNA, which is used as template for the synthesis of a large number of +RNA molecules. Newly synthesized +RNAs either enter a new round of genome replication or are packaged into capsid proteins to build infectious particles. Viruses are released by a non-lytic mechanism as well as upon cell lysis. Inhibitors of the different stages in the replication cycle are depicted in red.