Inhibition of amyloid fibril formation of human amylin by N-alkylated amino acid and α-hydroxy acid residue containing peptides

Amyloid deposits are formed as a result of uncontrolled aggregation of (poly)peptides or proteins. Today several diseases are known, for example Alzheimer's disease, Creutzfeldt-Jakob disease, mad cow disease, in which amyloid formation is involved. Amyloid fibrils are large aggregates of β-pleated sheets and here a general method is described to introduce molecular mutations in order to achieve disruption of β-sheet formation. Eight backbone-modified amylin derivatives, an amyloidogenic peptide involved in maturity onset diabetes, were synthesized. Their fi-sheet forming properties were studied by IR spectroscopy and electron microscopy. Modification of a crucial amide NH by an alkyl chain led to a complete loss of the β-sheet forming capacity of amylin. The resulting molecular mutated amylin derivative could.be used to break the β-sheet thus retarding β-sheet formation of unmodified amylin. Moreover, it was found that the replacement of this amide bond by an ester moiety suppressed fibrillogenesis significantly. Introduction of N-alkylated amino acids and/or ester functionalities-leading to depsipeptides-into amyloidogenic peptides opens new avenues towards novel peptidic β-sheet breakers for inhibition of β-amyloid aggregation.