Synthesis and activity of fibrillogenesis peptide inhibitors related to the 17–21 β-amyloid sequence

Peptide derivatives 1–5, incorporating synthetic non-proteinogenic amino acids, related to the β-amyloid 17–21 fragment of the amyloidogenic Aβ1–40, and the N-protected decapeptide 6, corresponding to a dimeric sequence of the same fragment, have been synthesized. These compounds were designed by using Soto's pentapeptide Ac–LPFFD–NH2 (iAβ5p) as lead compound. Their activity as inhibitors of fibrillogenesis and stability against enzymatic degradation have been determined. Compounds 1, 5 and 6 are potent inhibitors in comparison to the lead compound. Exposure to chymotrypsin of peptide derivatives 1–5, all containing unnatural amino acids, shows increased stability as compared with iAβ5p and 6. Conformational properties of the new compounds have been determined by CD and FT-IR spectroscopies.

Graphical abstract Synthesis, properties and activity of novel analogues (1–6) of the known Ac–Leu-Pro-Phe-Phe-Asp(OH)–NH2 (iAβ5p) fibrillogenesis pentapeptide inhibitor are reported.Figure optionsDownload full-size imageDownload as PowerPoint slide