Exploiting the Achilles' Heel of Viral RNA Processing to Develop Novel Antivirals

Abstract

Viruses continue to pose a significant health burden in the human population and recent history has shown a concerning surge in viral threats.Treatment options for viral infections are limited and viruses have proven adept at evolving resistance to existing therapies, highlighting a significant vulnerability in our defences. In response to this challenge,we explored the modulation of cellular RNA metabolic processes as an alternative paradigm to antiviral development. Many viruses depend on the host cell's RNA splicing machinery and small alterations in this host process results in catastrophic changes in virakl protein production, ultimately inhibiting virus replication. Previously, the small molecule 5342191 was identified as a potent inhibitor of HIV-1 replication by altering viral RNA accumulation at doses that minimally affect host cell gene expression. In this report, we document 5342191 as a potent inhibitor of adenovirus, coronavirus, and influenza replication. In each case, 5342191's reduction in virus replication was associated with altered viral RNA accumulation and loss of viral structural protein expression. Interestingly, while resistant viruses were rapidly isolated for compounds targeting either virus-encoded proteases or polymerases, we have not yet isolated 5342191-resistant variants of coronavirus or influenza.Like HIV-1, 5342191's inhibition of cornavirus and influenza is mediated through the activation of specific cell signaling networks, including GPCR and/or MAPK signaling pathways that ultimately affect SR kinase expression. Together, these studies highlight the therapeutic potential of compounds that target cellular processes essential for replication of multiple viruses. Not only do these compounds hold promise as broad-spectrum antivirals, but they also offer the potential for greater durability in combating viral infections.