Modulation of Saccharomyces cerevisiae Stm1_N1-113 and human AB42 amyloid fibril morphology by 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)-1H-benzimidazolium) dibromide

Abstract

Acridine derivatives are among the oldest and most effective classes of chemotherapeutic agents, exhibiting a broader spectrum of bioactivities like antitumor, antifungal, antimicrobial, and antiviral. They remain a preferred choice for molecular imaging of amyloid as well as for inhibiting amyloid fibrillation or stabilizing the fibril. This study reports the effect of a newly reported acridine compound 3,3-(acridine-4,5-diylbis(methylene)) bis(1-(carboxymethyl)-benzimidazolium) dibromide (henceforth, Ac-BIM-acid) on the amyloid-like fibrillation of N-terminal region of Saccharomyces cerevisiae Stm1 protein (Stm1_N1-113) and human A{beta}42. Modulation of Stm1_N1-113 amyloid-like structures at 400 {micro}M concentration with respect to varying concentrations of Ac-BIM-acid is revealed by AFM and NMR. While 2D-HSQC NMR spectra show the binding of Ac-BIM-acid with 400 {micro}M Stm1_N1-113, AFM captures the morphological changes of Stm1_N1-113 in response to 1 mM and 2.5 mM Ac-BIM-acid at physiological salt concentration in a time-dependent manner. Similarly, Ac-BIM-acid is shown to modulate the amyloid morphology of human A{beta}42 protein, responsible for Alzheimers disease, captured in AFM. Docking studies carried out indicate that the hydrophobic acridine ring binds at the hydrophobic pocket of the N-terminal {beta}-sheet and its neighboring {beta}-sheet of the A{beta}42 monomorphic fibril. Thus, Ac-BIM-acid would be yet another addition to the class of acridine derivatives that modulate amyloid fibrillation.