Chemical Perspective of the Mechanism of Action of Antiamyloidogenic Compounds Using a Minimalistic Peptide as a Reductionist Model.

The diphenylalanine (FF) residue which is present at the 19 and 20 positions of the amyloid beta (1-42) (Aβ42) peptide sequence is considered as a reductionist model for studying Aβ42 aggregation. FF self-assembles into well-ordered tubular structures via aromatic π-π stacking. Herein the manuscript, we have presented a chemical perspective on the mechanism of action of antiamyloid compounds by assessing their interaction with FF. Therefore, we first coincubated FF fibers with single amino acids, since they are constituted of different R side chains yet have a common structural unit. This study revealed a crucial role of aromatic rings and functional groups like thiol (-SH) in causing destabilization of FF assembly via their interaction with π-electrons participating in π-π stacking present in FF. We further studied the interaction of different nonsteroidal anti-inflammatory drugs (NSAIDs), other known antiamyloidogenic compounds, and host-guest inclusion compounds like cyclodextrin (CD) to assess their mechanism of action and to decipher the functional moiety present in these compounds which could cause destabilization of π-π stacking. From the coincubation experiments, we could surmise a crucial role of aromatic rings present in these compounds for causing interference in aromatic stacking. We further consolidated our observations through microscopy analysis by various spectroscopic methods such as aggregation-induced emission enhancement (AIEE), fluorescence spectroscopy, solution-state 1H NMR, FTIR, and circular dichroism. The studies presented in the manuscript thus provide significant insights into the role of functional groups in imparting antiamyloid action and open new avenues for an efficient design of antiamyloid drugs in the future.