Small-Molecule Strategies against Human Adenoviruses: Progress, Challenges, and Future Perspectives.

Human adenoviruses (HAdVs) present a significant health threat, particularly to immunocompromised individuals, where infections can progress to severe, life-threatening disease. Despite their clinical impact, no FDA-approved antiviral therapies specifically target HAdV infection. Current treatments, such as off-label cidofovir, are limited by nephrotoxicity, poor oral bioavailability, and resistance concerns, underscoring the urgent need for safer and more effective alternatives. This perspective critically evaluates recent advances in small-molecule anti-HAdV drug development, highlighting promising molecular scaffolds, innovative screening methodologies, and host-targeted strategies. Beyond repurposed drugs, we emphasize the importance of exploring diverse chemical spaces and integrating structure-based design with high-throughput phenotypic screening. By integrating insights from medicinal chemistry, virology, and pharmacology perspectives, the relevant challenges and strategic considerations to optimize anti-HAdV drug discovery and accelerate the translation of next-generation therapeutics into clinical application are discussed.