Emerging antiviral therapeutics for human adenovirus infection: Recent developments and novel strategies

Abstract

Human adenoviruses (HAdV) are ubiquitous human pathogens that cause a significant burden of respiratory, ocular, and gastrointestinal illnesses. Although HAdV infections are generally self-limiting, pediatric and immunocompromised individuals are at particular risk for developing severe disease. Currently, no approved antiviral therapies specific to HAdV exist. Recent outbreaks underscore the need for effective antiviral agents to treat life-threatening infections. In this review we will focus on recent developments in search of potential therapeutic agents for controlling HAdV infections, with a focus on those targeting post-entry stages of the virus replicative cycle.

Keywords: Adenovirus; Antiviral; Cidofovir; Drug repurposing; Drug synergy; Host-pathogen interactions; Outbreak; Synthetic-lethal.

Figure 1:. Potential antiviral therapeutics targeting the HAdV replicative cycle.

Candidate antivirals are shown in blue boxes with inhibitor arrows indicating where they function to disrupt the human adenovirus (HAdV) replicative cycle. 1) HAdV virions bind to cell surface receptors to mediate internalization into endosomes. 2) virions escape the endosome, tearing off fiber proteins in the process, and use microtubules to traffic to the 3) nuclear pore complexes (NPC) to release their genome. 4) HAdV gene expression occurs via transcription of the genome into mRNA. Gene expression inhibitors, epigenetic-based inhibitors, and cyclin-dependent kinase (CDK) inhibitors target the transcriptional process. mRNA are exported into the cytoplasm for translation into both early and late viral proteins, which are imported back into the nucleus. 5) HAdV protein-primed genome replication occurs, a process targeted by protease inhibitors. DNA synthesis of new viral genomes is disrupted by cidofovir-based derivatives and other DNA synthesis inhibitors. 6) virion assembly occurs in the nucleus, with the newly produced viral genomes assembled with late HAdV structural proteins. Protease inhibitors target the protease-driven maturation of these structural proteins. 7) Viral egress is triggered by cell lysis, induced by adenovirus death protein (ADP) in some HAdV species, and could be targeted by egress inhibitors. Created with BioRender.com