Marasco_2021_Chem.Biol.Interact_334_109300

Herein we present a comparative study of the effects of isoquinoline alkaloids belonging to benzo[c]phenanthridine and berberine families on beta-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 Abeta(1-42) aggregation. Conversely, coralyne, that contains the isomeric berberine nucleus, significantly increased propensity for Abeta(1-42) to aggregate. Surface Plasmon Resonance (SPR) experiments provided quantitative estimation of these interactions: coralyne bound to Abeta(1-42) with an affinity (K(D) = 11.6 microM) higher than benzo[c]phenanthridines. Molecular docking studies confirmed that all three compounds are able to recognize Abeta(1-42) in different aggregation forms suggesting their effective capacity to modulate the Abeta(1-42) self-recognition mechanism. Molecular dynamics simulations indicated that coralyne increased the beta-content of Abeta(1-42), in early stages of aggregation, consistent with fluorescence-based promotion of the Abeta(1-42) self-recognition mechanism by this alkaloid. At the same time, sanguinarine induced Abeta(1-42) helical conformation corroborating its ability to delay aggregation as experimentally proved in vitro. The investigated compounds were shown to interfere with aggregation of Abeta(1-42) demonstrating their potential as starting leads for the development of therapeutic strategies in neurodegenerative diseases.