Identification of a New Function of Cardiovascular Disease Drug 3-Morpholinosydnonimine Hydrochloride as an Amyloid-β Aggregation Inhibitor

Abstract

Cardiovascular disease (CVD) and Alzheimer’s disease (AD) have a mutual cause-and-effect relationship, and they share some common risk factors. Although numerous Food and Drug Administration (FDA)-approved drugs have been developed for CVD treatment, no drugs are clinically available for AD treatment. Given the common disease-causing factors and links between the two diseases and the well-demonstrated drugs for CVD, we propose to re-examine the new potential of the existing CVD drugs as amyloid-β (Aβ) inhibitors. 3-Morpholinosydnonimine hydrochloride (SIN-1) is an FDA-approved drug for inhibiting platelet aggregation in CVD. Herein, we examine the inhibition activity of SIN-1 on the aggregation and toxicity of Aβ _1–42 using combined experimental and computational approaches. Collective experimental data from ThT, circular dichroism, and atomic force microscopy demonstrate that SIN-1 can effectively inhibit amyloid formation at every stage of Aβ aggregation by prolonging lag phase, slowing down aggregation rate, and reducing final fibril formation. The cell viability assay also shows that SIN-1 enables the protection of SH-SY5Y cells from Aβ-induced cell toxicity. Such an inhibition effect is attributed to interference with the structural transition of Aβ toward a β-sheet structure by SIN-1. Furthermore, molecular dynamic simulations confirm that SIN-1 preferentially binds to the C-terminal β-sheet grooves of an Aβ oligomer and consequently disrupts the β-sheet structure of Aβ and Aβ–Aβ association, explaining experimental observations. This work discovers a new function of SIN-1, making it a promising compound with dual protective roles in inhibiting both platelet and Aβ aggregations against CVD and AD.