Viroporins beyond pathogenesis: Ion channel properties as the key to unlocking a neglected antiviral target

A class of proteins encoded by viral genomes, referred to as viroporins, is composed of small hydrophobic proteins that form pores or ion channels in host membranes. These proteins modulate the viral life cycle and pathogenicity. Despite their early discovery and functional significance, viroporins have long remained underexploited as antiviral drug targets-partly due to the emergence of alternative antiviral strategies, viral evolutionary complexity, and technical limitations in studying channel function. Nonetheless, accumulating evidence underscores their essential roles in pathogenesis and viral fitness, positioning them as promising but underdeveloped therapeutic targets. While recent reviews have revisited the field, most have focused on the pathological functions of viroporins, with little attention given to the fundamental biophysical properties that define them as ion channels. Given that channel function is intrinsically governed by attributes such as ion selectivity and gating mechanisms, a mechanistic understanding of these properties is critical for understanding the pathogenic mechanism and rational drug development. To our knowledge, no prior review has systematically addressed viroporins from a channel-centric perspective. Here, we propose a reclassification framework grounded in the core biophysical attributes of viral channels, highlighting their ion permeability, gating behavior, and regulatory features. By shifting the focus from pathophysiology to channel function, this work aims to provide a conceptual foundation for future antiviral strategies and to stimulate broader interest in this underexplored but compelling class of viral targets.