Modulation of Saccharomyces cerevisiae Stm1_N ^1-113 and human Aβ42 amyloid fibril morphology by 3,3’-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)-1H-benzimidazolium) dibromide

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 fibrillation of N-terminal region of Saccharomyces cerevisiae Stm1 protein (Stm1_N ^1-113 ) and human Aβ42. Modulation of Stm1_N ^1-113 amyloid structures (at 400 µM concentration) with respect to varying concentrations of Ac-BIM-acid is revealed by AFM and NMR (0.5 mM, 1 mM, and 2.5 mM). While 2D-HSQC NMR spectra show the binding of Ac-BIM-acid with 400 µM Stm1_N ^1-113 , AFM captures the morphological changes of Stm1_N ^1-113 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 Aβ42 protein, responsible for Alzheimer’s disease, captured in AFM. Docking studies carried out indicate that the hydrophobic acridine ring binds at the hydrophobic pocket of the N-terminal β-sheet and it’s neighboring β-sheet of the Aβ42 monomorphic fibril. Thus, Ac-BIM-acid would be yet another addition to the class of acridine derivatives that modulate amyloid fibrillation.