Abnormal misfolding and aggregation of amyloid proteins are the pathological hallmarks of many neurodegenerative disorders including Alzheimer’s disease (AD) and Type 2 diabetes (T2D). While significant efforts and progress have been made to develop a wide range of compounds to interfere with amyloid aggregation and toxicity, most of compounds only target a specific disease-related amyloid protein. Considering that a potential link between AD and T2D from clinical studies, herein we developed a data-driven drug-repurposing strategy to computationally discover and experimental validate some existing drugs, which serve as (i) dual-functional inhibitors (e.g. genistein and tanshinones) to prevent the formation of both Aβ and hIAPP fibrils, disaggregate the preformed mature fibrils, and alleviate the amyloid-induced cytotoxicity and (ii) dual-functional promoter (e.g. aromadendrin) to accelerate the aggregation process of both Aβ and hIAPP and remodel toxic amyloids by quickly bypassing the toxic oligomer formation stage. Further molecular dynamics simulations revealed different binding mechanisms of these drugs to amyloid aggregates, thus explaining their amyloid inhibition or acceleration behaviors as observed by experiments. Different from traditional single-target amyloid modulators, this work provides a new strategy to identify the existing drugs with new and sequence-independent modulation function against different amyloid proteins.

Dual-functional amyloid modulators of both amyloid β and human islet amylin peptides

ACS Spring Meeting 2021

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