Amyloid Pan-inhibitors: One Family of Compounds To Cope with All Conformational Diseases

Abstract

Amyloids are ubiquitous protein aggregates sharing common internal structural features; they are present in all organisms, from prokaryotes to eukaryotes, where they play physiological or pathological roles. Importantly, amyloids, which are generated by aggregation of a range of distinct proteins, could be a key factor in a number of major human disorders, the so-called conformational diseases. Because all amyloids exhibit similar cross-β motifs, one may envisage that molecules capable of blocking the formation of β-sheet structures could abolish aggregation of all amyloid proteins, albeit with different efficacies. Herein, two different β-sheet blockers were tested against a selection of amyloidogenic proteins, encompassing all the major types of amyloid-based disorders. Analysis of their blocking efficiency, using a simple but contrasted cell-based screening procedure, unequivocally confirms that they indeed behave as aggregation pan-inhibitors. The significant inhibitory effects observed for these compounds against all tested amyloidogenic proteins could spur a broader biological evaluation of other known and new amyloid aggregation inhibitors to further determine the potential use of this class of compounds for the universal treatment of conformational diseases.

A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors

“…When tested at an inhibitor concentration of 10 µM, low percentages of inhibition were found both for Aβ42 (up to 12%) and for tau (up to 23%) (Table 1), so these compounds are weak antiaggregating compounds. We had found very similar results in other tacrine-and 6chlorotacrine-based hybrids that feature a cycloaliphatic ring as the second pharmacophoric moiety [51], whereas much better anti-aggregating activities were found for 6-chlorotacrine-and huprine-based hybrids bearing as the second pharmacophore a polycyclic heteroaromatic system [52,53,67]. Thus, the presence of an extended aromatic system, apart from that of 6-chlorotacrine or huprine, seems to be a favourable structural requirement in this class of hybrid compounds for a good antiaggregating activity of Aβ42, tau, and other amyloidogenic protein involved in other major human disorders [67].…”

New Pyrimidine and Pyridine Derivatives as Multitarget Cholinesterase Inhibitors: Design, Synthesis, and In Vitro and In Cellulo Evaluation

“…Low percentages of inhibition were found both on Aβ 42 (up to 22%) and on tau (up to 17%), so these compounds have a weak anti-aggregating activity when compared with the reference compound DP-128. 37 The pyridine derivative 28 is the best inhibitor of aggregation of both Aβ 42 and tau, while the pyrimidine 13 showed a similar percentage of inhibition on Aβ 42 aggregation but lower toward tau.…”

Pharmacophore Modeling and 3D-QSAR Study of Indole and Isatin Derivatives as Antiamyloidogenic Agents Targeting Alzheimer’s Disease

“…The role of tau hyperphosphorylation and aggregation in AD has established both of them as a target for therapeutic intervention [8], although only N,N,N',N'-tetramethyl-10H-phenothiazine-3,7-diaminium (TRX0237, leucomethylthioninium), the reduced form of methylene blue dye, acting as an inhibitor of tau aggregation, has reached the clinical phase III [26]. In recent years, some of us developed an efficient cell-based assay of tau aggregation, a simple and inexpensive method that provides a straightforward assay to evaluate the putative anti-aggregation capacity of small molecules [27][28][29]. This method relies on the use of bacteria overexpressing amyloid-prone proteins to monitor the amyloid aggregation, thus constituting a physiologically relevant model.…”

“…Because of the addition of the initiation codon ATG in front of gene, the over-expressed protein contains an additional methionine residue at its N terminus. Tau anti-aggregating activities of the target compounds were assessed in E. coli cells, as previously described [27][28][29]. M9 minimal medium (10 mL) containing 0.5% of glucose, 100 µg/mL of ampicillin and 12.5 µg/mL of chloramphenicol was inoculated with a colony of BL21 (DE3) cells bearing the plasmids.…”