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

Abstract

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.

Controlled aggregation properties of single amino acids modified with protecting groups

“…Tannic acid is a well-known amyloid inhibitor that disrupts pi-pi stacking. 25,40 The assemblies formed by modified aliphatic and aromatic single amino acids were disrupted upon co-incubation with tannic acid which clearly suggested the crucial role of p-p stacking in the assembly formation which is facilitated by the presence of an Fmoc group present in aliphatic single amino acids. Urea is a well-known hydrogen bond breaker.…”

“…19 Kuo and coworkers recently employed the selfassembly of polypeptide diblock copolymers for the fabrication of high capacitance microporous carbon. [20][21][22] Our group is interested in studying the self-assembly of single amino acids, [23][24][25][26] peptides, [27][28][29][30][31][32] and heterocyclic compounds. [33][34][35] Hence, motivated by our previous research interest wherein we illustrated the self-assembly of single amino acids, [23][24][25][26] we were curious to study the self-assembled structure formation by modified single amino acids as well.…”

“…[20][21][22] Our group is interested in studying the self-assembly of single amino acids, [23][24][25][26] peptides, [27][28][29][30][31][32] and heterocyclic compounds. [33][34][35] Hence, motivated by our previous research interest wherein we illustrated the self-assembly of single amino acids, [23][24][25][26] we were curious to study the self-assembled structure formation by modified single amino acids as well. Therefore, we comprehensively assessed the self-assembling properties of single amino acids by functionalizing them with various protecting groups.…”

Unusual Aggregates Formed by the Self-Assembly of Proline, Hydroxyproline, and Lysine

“…19 Gazit et al also recently studied the single-crystal structures of amino acids and explained the formation of layered secondary structures by their supramolecular association. 20 Our group has been interested in studying the self-assembly of single amino acids, 6,21,22 peptides, 23−25 oligonucleotides, 23 biopolymers, 26 and heterocyclic molecules. 27,28 Herein we report the self-assembled aggregates formed by the single amino acids Pro, Hyp, and Lys to ordered structures which show morphological transition with varying concentration and aging time.…”

Influence of the Alcoholic/Ethanolic Extract of Mangifera indica Residues on the Green Synthesis of FeO Nanoparticles and Their Application for the Remediation of Agricultural Soils

“…The development of these ecosystem-friendly methods for nanoparticle synthesis has become an important branch of nanotechnology: "green synthesis" [25,26]. Plant or fruit extracts contain phytochemicals and metabolites that give them unique properties, which can be used as reducing agents for the synthesis and stabilization of nanoparticles [13,27].…”