Targeting the IL-17A Cytokine Interface: Structural Insights and Small-Molecule Modulators

Abstract Interleukin-17A (IL-17A) is a proinflammatory cytokine that occupies a central position at the interface of host defense, tissue homeostasis, and chronic inflammation. While IL-17A plays essential roles in antimicrobial immunity and epithelial barrier integrity, dysregulated IL-17A signaling drives the pathogenesis of autoimmune and inflammatory diseases. This functional duality underlies both the clinical success and the inherent limitations of IL-17A signaling-neutralizing therapies, highlighting the need for selective and context-dependent modulation. In this perspective, we provide an overview of IL-17A signaling, from cytokine production to receptor-proximal signal transduction and therapeutic intervention. We then discuss small-molecule IL-17A antagonists identified through structure-guided approaches, with an emphasis on key binding modes, and briefly summarize compounds discovered through assay-based strategies. Beyond antagonism, we also examine the emerging concept of IL-17RA agonism, which remains largely unexplored. Collectively, this perspective highlights the importance of context-dependent small-molecule modulation of IL-17A signaling.