β-Sheet Breaker Peptides Containing α,β-Dehydrophenylalanine: Synthesis and In Vitro Activity Studies

The synthesis and fibrillogenesis‐inhibiting activity of the new peptide derivatives 1–6, containing α,β‐unsaturated phenylalanines, are reported. These compounds are related to the pentapeptide Ac‐LPFFD‐NH2 (iAβ5p), which was designed by Soto and co‐workers and is commonly accepted as a lead compound for fibrillogenesis inhibition . Their activities are determined by Thioflavin T binding assay, far‐UV circular dichroism (CD) spectroscopy , and SEM; in addition, their structures in solution are studied through far‐UV CD and FTIR spectroscopy. The presence of two α,β‐unsaturated phenylalanines increases the fibrillogenesis inhibiting activity significantly in comparison with the lead compound. The interactions between the Aβ1–40 and the inhibitors using electrospray ionization mass spectrometry are also studied. The analyses prove the presence of noncovalent complexes of Aβ1–40 with iAβ5p and its derivatives 1–3 with stoichiometries of 1:1 and 2:1, and the results are independent of time and Aβ1–40/inhibitor ratio. β‐Sheet breaker inhibitors: Six new pseudopeptides containing α,β‐unsaturated phenylalanines (ΔPhe), related to the pentapeptide Ac‐LPFFD‐NH2, were synthesized and tested as fibrillogenesis inhibitors by Thioflavin T binding assay, far‐UV circular dichroism spectroscopy, ESI‐MS, and SEM. The presence of two consecutive ΔPhe moieties increases the inhibiting activity significantly compared with that of the lead compound.