RESUMO
The development of generic inhibitors in order to control the formation of amyloid fibrils and early oligomers is still an unmet medical need. As it is hypothesized that amyloid assemblies represent a generic protein supramolecular structure of low free energy, targeting the key molecular recognition and self-assembly events may provide the route for the development of such potential therapeutic agents. We have previously demonstrated the ability of hybrid molecules composed of an aromatic moiety and the α-aminoisobutyric acid ß-sheet breaker elements to act as excellent inhibitors of amyloid fibril formation. Specifically, the D-Trp-Aib was shown to be a superb inhibitor of the formation of Alzheimer's disease ß-amyloid fibrils and oligomers both in vitro and in vivo. Here, we demonstrate that the rationally designed molecule has the generic ability to inhibit amyloid fibril formation by calcitonin, α-synuclein, and the islet amyloid polypeptide. Moreover, we demonstrate the inability of two modified peptides, D-Ala-Aib and D-Trp-Ala, to inhibit and disassemble amyloid fibril formation, a fact that provides an additional evidence for the suggested structural basis of the inhibitor activity. Taken together, we believe that the use of ß-breaker elements combined with aromatic moiety may present a promising approach for the development of fibrillization inhibition drug candidate.
