Inhibition of Amyloid Peptide Fragment Aβ25-35 Fibrillogenesis and Toxicity by N-Terminal β-Amino Acid-Containing Esapeptides: Is Taurine Moiety Essential for In Vivo Effects?

We report the synthesis and fibrillogenesis inhibiting activity of the new peptide derivatives 14, related to the pentapeptide Ac-LPFFD-NH2 (iA beta 5p), proposed by Soto and co-workers and widely recognized as one of the most active beta-sheet breaker agents. The A beta 2535 fragment of the parent full-length A beta 142 was used as fibrillogenesis model. The activity of peptide derivatives 14 was tested in vitro by thioflavin T binding assay, far UV CD spectroscopy, and scanning electron microscopy. Their ability to hinder the toxic effect of A beta 2535in vivo was studied by monitoring the viability of human SH-SY5Y neuroblastoma cells and the prevention of superoxide anion radical release from BV2 microglial cells. The results point to a favourable role in the fibrillogenesis inhibitory activity of the sulphonamide junction for compounds 1 and 2, containing an N,N-dimethyltaurine and a taurine amino-terminal moiety, respectively. Furthermore, compounds 1 and 2 show a significant protective effect on cell viability, rescuing the cells from the toxicity exerted by A beta 2535 treatment.