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bioRxiv · 10.1101/2025.08.04.668593

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

Uttamrao, P. P.·Das, U.·Kumar, R. R.·Harijan, D.·Balu, A. K.·Rao, D. K.·Prabusankar, G.·Rathinavelan, T.
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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.

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Uttamrao, P. P., Das, U., Kumar, R. R., Harijan, D., Balu, A. K., Rao, D. K., Prabusankar, G., Rathinavelan, T.. 2025-08-06. 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. https://doi.org/10.1101/2025.08.04.668593

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