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Conclusions
Material and methods
Conflicts of interest
Acknowledgements
Introduction Currently more than 30 human proteins are implicated in a range of degenerative disorders owing to their misfolding and misassembly into various aggregate structures and leading to at least 20 serious human diseases named amyloidosis [[1], [1]a), [1]b), [1]c), [1]d), [1]e)]. The self-assembled insoluble NVP-BGJ398 phosphate mg are characterized by highly ordered cross-β structures [1]. In particular, Alzheimer's disease (AD) is associated with the aggregation of the amyloid-β (Aβ1-42) peptide into senile plaques in the brain [[2], [2]a), [2]b)]. Approximately 47 million people worldwide are living with AD and this number is expected to reach 75 million by 2030, and 135.5 million by 2050 [3]. Yet, despite significant means implemented, no causal treatment exists nor for AD nor for the other amyloid diseases. Many efforts have been made to design drugs targeting the amyloid cascade in AD but they have failed in clinical trials [[4], [4]a), [4]b), [4]c)]. An ongoing promising strategy to find a therapy for AD involves the search for compounds that can inhibit Aβ1-42 aggregation, to be used very early before the symptoms appear and before brain pathology (amyloid-plaques and tau tangles) [4c]. However, designing small molecular inhibitors that disrupt protein−protein interactions mediating the aggregation is still a challenge [1]. Indeed, protein−protein interactions occur over large surface areas that are difficult to characterize. Furthermore, many different forms of aggregates are produced while their structures and toxicity are far to be elucidated [[5], [5]a), [5]b), [5]c)]. In particular, while the monomeric form of Aβ1-42 is currently declared as non toxic, fibrils are able to generate damaging redox activity and promote the nucleation of toxic oligomers [[6], [6]a), [6]b), [6]c)]. Recent studies demonstrate that soluble transient oligomers preceding fibril formation are highly toxic species constitute a major target to prevent the death of neurons [[7], [7]a), [7](b), [7](c), [7](d), [7]e)]. A large number of small molecules (e.g., tramiprosate, inositol, curcumin, epigallocatechin-3-gallate and resveratrol) have been reported as Aβ1-42 inhibitors and have been studied in clinical trials [5,8]. However, the majority of these agents bind to Aβ1-42 with low affinity, without selectivity and have no or unknown effect on the most toxic oligomeric species. Recently various monoclonal antibodies (such as Solanezumab) have been produced to inhibit Aβ1-42 aggregation by targeting soluble species of the peptide. However they failed to show clinical efficacy in phase II or III clinical trials probably mainly because of their failure to cross the blood-brain barrier (BBB) due to their large size [4a]. Peptide-based drug discovery could be a serious option for addressing new therapeutic challenging candidates. The number of approved peptides is dramatically increasing, in particular because they often offer greater efficacy, selectivity, specificity and a reduced risk of unforeseen side-reactions compared to small organic molecules [[9], [9]a), [9](b), [9]c), [9]d)]. Modified peptides and peptidomimetics can also be designed to decrease the susceptibility to proteases and to cross the BBB. A variety of small peptides or modified peptides that inhibit aggregation of Aβ and reduce its toxic effects have been already described [4]a), [10]f), [10]g), [10]h), [10], [10]a), [10]b), [10]c), [10]d), [10]e). However, the use of pre-structured peptides, in particular small acyclic β-hairpins has been very rarely explored as β-sheet binders and inhibitors of aggregation [11]. We firmly believe that the greater flexibility of such compounds with respect to the cyclic peptides, allows them to adapt to the different shape of the various aggregated forms of the amyloid peptide. As a result, they can better bind to the sequences involved in the β-sheet structures of the amyloid peptide.