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

Peptide derivatives 1-5, incorporating synthetic non-proteinogenic amino acids, related to the beta-amyloid 17-21 fragment of the amyloidogenic A beta(1-40), 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 (iA beta 5p) 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 iA beta 5p and 6. Conformational properties of the new compounds have been determined by CD and FF-IR spectroscopies. (C) 2008 Elsevier Masson SAS. All rights reserved.