Abstract
Herein we present a comparative study of the effects of isoquinoline alkaloids belonging to benzo[c]phenanthridine and berberine families on β-amyloid aggregation. Results obtained using a Thioflavine T (ThT) fluorescence assay and circular dichroism (CD) spectroscopy suggested that the benzo[c]phenanthridine nucleus, present in both sanguinarine and chelerythrine molecules, was directly involved in an inhibitory effect of Aβ1-42 aggregation. Conversely, coralyne, that contains the isomeric berberine nucleus, significantly increased propensity for Aβ1-42 to aggregate. Surface Plasmon Resonance (SPR) experiments provided quantitative estimation of these interactions: coralyne bound to Aβ1-42 with an affinity (KD = 11.6 μM) higher than benzo[c]phenanthridines. Molecular docking studies confirmed that all three compounds are able to recognize Aβ1-42 in different aggregation forms suggesting their effective capacity to modulate the Aβ1-42 self-recognition mechanism. Molecular dynamics simulations indicated that coralyne increased the β-content of Aβ1-42, in early stages of aggregation, consistent with fluorescence-based promotion of the Aβ1-42 self-recognition mechanism by this alkaloid. At the same time, sanguinarine induced Aβ1-42 helical conformation corroborating its ability to delay aggregation as experimentally proved in vitro. The investigated compounds were shown to interfere with aggregation of Aβ1-42 demonstrating their potential as starting leads for the development of therapeutic strategies in neurodegenerative diseases.