Recent advances in small molecules for amyloid fibril inhibition: chemical strategies and molecular mechanistic insights from lysozyme and insulin models.

Protein misfolding and aggregation are central pathological processes underlying amyloidosis, a group of disorders characterized by the deposition of insoluble amyloid fibrils. These toxic aggregates form due to conformational destabilization and exposure of hydrophobic protein regions, leading to aberrant interactions that disrupt normal cellular functions. Amyloid fibrillation is a key pathological event in both neurodegenerative and systemic disorders. In metabolic and systemic amyloidosis, such as lysozyme derived and insulin derived amyloidosis, peripheral fibril deposition leads to progressive organ dysfunction, while cerebral amyloid accumulation is associated with neurodegenerative diseases like Alzheimer's. To inhibit protein aggregation and destabilize preformed fibrils, a wide range of amyloid inhibitors has been explored. While naturally derived molecules offer some anti-amyloid activity, their limitations have driven growing interest in synthetic and semi-synthetic organic molecules, repurposed drugs, organic dyes, and short peptides. These agents offer enhanced chemical versatility, improved biocompatibility, and the ability to modulate multiple stages of amyloid aggregation. This review provides an overview of the molecular mechanisms of protein misfolding and recent advances in the molecular design, structure-activity relationships, and evaluation of synthetic and semi-synthetic amyloid inhibitors. Using lysozyme and insulin as model systems, we highlight emerging strategies for anti-amyloidogenic intervention.