Acyclic β-hairpins designed on oligomeric and fibril structures of Aβ1–42 disrupt protein–protein interactions mediating amyloid β-peptide aggregation.

How anti-Alzheimer's drug candidates that reduce amyloid 1-42 peptide fibrillization interact with the most neurotoxic species is far from being understood. We report herein the capacity of sugar-based peptidomimetics to inhibit both Aβ1-42 early oligomerization and fibrillization. A wide range of bio- and physicochemical techniques, such as a new capillary electrophoresis method, nuclear magnetic resonance, and surface plasmon resonance, were used to identify how these new molecules can delay the aggregation of Aβ1-42. We demonstrate that these molecules interact with soluble oligomers in order to maintain the presence of nontoxic monomers and to prevent fibrillization. These compounds totally suppress the toxicity of Aβ1-42 toward SH-SY5Y neuroblastoma cells, even at substoichiometric concentrations. Furthermore, demonstration that the best molecule combines hydrophobic moieties, hydrogen bond donors and acceptors, ammonium groups, and a hydrophilic β-sheet breaker element provides valuable insight for the future structure-based design of inhibitors of Aβ1-42 aggregation.

No abstract

Alzheimer’s disease (AD) represents a progressive amyloidogenic disorder whose advancement is widely recognized to be connected to amyloid-β peptides and Tau aggregation. However, several other processes likely contribute to the development of AD and some of them might be related to protein-protein interactions. Amyloid aggregates usually contain not only single type of amyloid protein, but also other type of proteins and this phenomenon can be rationally explained by the process of protein cross-seeding and co-assembly. Amyloid cross-interaction is ubiquitous in amyloid fibril formation and so a better knowledge of the amyloid interactome could help to further understand the mechanisms of amyloid related diseases. In this review, we discuss about the cross-interactions of amyloid-β peptides, and in particular Aβ1-42, with other amyloids, which have been presented either as integrated part of Aβ neurotoxicity process (such as Tau) or conversely with a preventive role in AD pathogenesis by directly binding to Aβ (such as transthyretin, cystatin C and apolipoprotein A1). Particularly, we will focus on all the possible therapeutic strategies aiming to rescue the Aβ toxicity by taking inspiration from these protein-protein interactions.

Misfolding and aggregation of amyloid b1-42 peptide( A b1-42) play ac entral role in the pathogenesis of Alzheimer's disease (AD). Ta rgeting the highly cytotoxic oligomeric species formed during the early stages of the aggregation process represents ap romising therapeutic strategy to reduce the toxicity associated with Ab1-42. Currently,t he thioflavin T( ThT) assay is the only established spectrofluorometric methodt os creen aggregation inhibitors. The successo ft he ThT assay is that it can detect Ab1-42 aggregates with high b-sheet content,s uch as protofibrils or fibrils, which appear in the late aggregation steps. Unfortunately,b yu sing the ThT assay,t he detection of inhibitors of early soluble oligomers that present al ow b-sheet character is challenging. Herein, an ew,f acile, and robust boron-dipyrromethene( BODIPY) real-time assay suitable for 96-well plate format, which allows screening of compounds as selectivei nhibitors of the formation of Ab1-42 oligomers, is reported.T hese inhibitors decrease the cellular toxicityo fA b1-42, although they fail in the ThT assay.T he findings have been confirmed and validated by structural analysis and cell viability assays under comparable experimental conditions. It is demonstrated that the BODIPY assay is ac onvenient methodt o screen and discover new candidate compoundst hat slow down or stop the pathological earlyo ligomerization process and are active in the cellular assay.T herefore, it is as uitable complementary screening method of the current ThT assay.Alzheimer's disease (AD) is ad evastating neurodegenerative disease that leads to progressive cognitive decline, functional impairment, and loss of independence. [1] The number of people worldwide suffering from AD is expected to reach 75 million by 2030, [2] butn oc ausative treatment exists for AD.The search for small molecules that inhibitt he aggregation of the 42-residue amyloid b protein fragment (Ab1-42; Figure 1A) is still ongoing to find at herapy for AD. Ab1-42 spontaneously self-associates into soluble oligomers and insolublea ggregates, such as protofibrilsa nd fibrils with high b-sheetc ontent.I th as been recognized that small and soluble Ab1-42 oligomers are particularly cytotoxic. [3][4][5][6][7] Thus, therapeutics trategies that intervene in the early oligomerization process, rather than in the later fibril formation step, have recently attracted attention. [8] However,d espite its therapeutic significance,t he screening of potentiali nhibitors of the early oligomerization process is still challenging. The thioflavin T( ThT) fluorescencea ssayi su sed routinelytodetermine the influence of compounds on amyloid aggregation kinetics. [9,10] However,T hT only exhibits as ubstantial fluorescencei ncreaseu pon binding to b-sheet-rich amyloid protofilaments and fibrils, but has low sensitivity to soluble early-stage oligomers. [11][12][13][14] Molecules that do not show any apparenti nhibition of amyloid aggregation,a ccording to the ThT assay,a re usually not considered for any subsequentt est...

A major current issue in medicinal chemistry is the design of small peptide analogues resistant to proteolysis and able to adopt preferential conformations, while preserving the selectivity and efficiency of natural peptides.

Natural compounds, such as plant and fruit extracts have shown neuroprotective effect against neurodegenerative diseases. It has been reported that several natural compounds binding to transthyretin (TTR) can be useful in amyloidosis prevention. TTR is a transporter protein that under physiological condition carries thyroxine (T 4 ) and retinol in plasma and in cerebrospinal fluid (CSF); it also has a neuroprotective role against Alzheimer's disease (AD). However, TTR also is an amyloidogenic protein responsible for familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC). The TTR amyloidogenic potential is speeded up by several point mutations. One therapeutic strategy against TTR amyloidosis is the stabilisation of the native tetramer by natural compounds and small molecules. In this review, we examine the natural products that, starting from 2012 to present, have been studied as a stabiliser of TTR tetramer. In particular, we discussed the chemical and structural features which will be helpful for future drug design of new TTR stabilisers.

Amyloid diseases are degenerative pathologies, highly prevalent today because they are closely related to aging, that have in common the erroneous folding of intrinsically disordered proteins (IDPs) which aggregate and lead to cell death. Type 2 Diabetes involves a peptide called human islet amyloid polypeptide (hIAPP), which undergoes a conformational change, triggering the aggregation process leading to amyloid aggregates and fibers rich in β-sheets mainly found in the pancreas of all diabetic patients. Inhibiting the aggregation of amyloid proteins has emerged as a relevant therapeutic approach and we have recently developed the design of acyclic flexible hairpins based on peptidic recognition sequences of the amyloid β peptide (Aβ1–42) as a successful strategy to inhibit its aggregation involved in Alzheimer’s disease. The present work reports the extension of our strategy to hIAPP aggregation inhibitors. The design, synthesis, conformational analyses, and biophysical evaluations of dynamic β-hairpin like structures built on a piperidine-pyrrolidine β-turn inducer are described. By linking to this β-turn inducer three different arms (i) pentapeptide, (ii) tripeptide, and (iii) α/aza/aza/pseudotripeptide, we demonstrate that the careful selection of the peptide-based arms from the sequence of hIAPP allowed to selectively modulate its aggregation, while the peptide character can be decreased. Biophysical assays combining, Thioflavin-T fluorescence, transmission electronic microscopy, capillary electrophoresis, and mass spectrometry showed that the designed compounds inhibit both the oligomerization and the fibrillization of hIAPP. They are also capable to decrease the aggregation process in the presence of membrane models and to strongly delay the membrane-leakage induced by hIAPP. More generally, this work provides the proof of concept that our rational design is a versatile and relevant strategy for developing efficient and selective inhibitors of aggregation of amyloidogenic proteins.