Accumulating evidences have shown a strong pathological relationship between cardiovascular disease (CVD) and protein misfolding diseases (PMDs) including Alzheimer’s diseases (AD) and Type II diabetes (T2D) as indicated by sharing many common symptoms and mutually contribute to each other. Given such close correlation between CVD and PMDs, we proposed to re-purpose CVD drugs as amyloid inhibitors against its abnormal misfolding and aggregation, which is considered as a common and critical pathological event in PMDs. In this work, we discovered two CVD drugs of cloridarol as hIAPP inhibitor (associated with T2D) and SIN-1 as Aβ inhibitor (associated with Aβ), respectively. Collective aggregation data from ThT assays, AFM images, CD spectra confirmed that both CVD drugs exhibited a dose-dependent inhibition property against (i) hIAPP and Aβ aggregation by 57-70% and (ii) hIAPP- and Aβ-induced cell toxicity by 3-25%. Furthermore, comparative molecular dynamics simulations revealed a possible common inhibition mechanism that both cloridarol and SIN-1 preferentially bound to C-terminal β-sheet region of hIAPP/Aβ through a combination of hydrophobic interactions, π-π stacking, and hydrogen bonding, which allow CVD drugs to disturb hIAPP/Aβ structure and β-structure content, weaken the hIAPP–hIAPP/Aβ-Aβ interaction, and block hIAPP/Aβ lateral association pathway. In a broader view, given well-established pharmaceutical functions of CVD drugs (non-toxic, biocompatible, nerve cell-targeting properties), drug repurposing could serve as a promising strategy for the future development of amyloid inhibitors for amyloid disease treatments.

Repurposing cardiovascular disease drugs as amyloid inhibitors

ACS Fall 2021

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