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

Peptide derivatives 1e5, incorporating synthetic non-proteinogenic amino acids, related to the b-amyloid 17e21 fragment of the amyloidogenic Ab1e40, 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 AceLPFFDeNH2 (iAb5p) 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 1e5, all containing unnatural amino acids, shows increased stability as compared with iAb5p and 6. Conformational properties of the new compounds have been determined by CD and FT-IR spectroscopies.