Covalent small-molecule RNA targeting in Alzheimer's disease: Computational strategies, challenges and opportunities

RNA dysfunction is increasingly recognized as an upstream driver of Alzheimer's disease pathology, and covalent small molecules that engage pathogenic RNA structures are emerging as a therapeutic strategy. In addition to its role as a template, RNA governs amyloid-β production, the tau isoform balance and neuroinflammation through aberrant splicing, noncoding RNA activity and epitranscriptomic modification. The irreversible engagement of these structures enables modulation with sustained target occupancy. This analysis examines how covalent docking, molecular dynamics and AI-enabled screening can be combined to identify electrophilic RNA binders, using the microtubule-associated protein tau exon 10 splicing regulatory element and the amyloid precursor protein 5'-UTR as concrete reference points. It assesses the determinants of nucleophilic reactivity in folded RNA, the electrophilic modules with demonstrated RNA reactivity and the barriers of selectivity, brain delivery and translational validation.