CONTROLLING AMYLOID BETA -PEPTIDE FIBRIL FORMATION WITH PROTEASE-STABLE LIGANDS

Abstract We have previously shown that short peptides incorporating the sequence KLVFF can bind to the ∼40amino acid residue Alzheimer amyloid β-peptide (Aβ) and disrupt amyloid fibril formation (Tjernberg, L. O., Naslund, J., Lindqvist, F., Johansson, J., Karlstrom, A. R., Thyberg, J., Terenius, L., and Nordstedt, C. (1996) J. Biol. Chem. 271, 8545–8548). Here, it is shown that KLVFF binds stereospecifically to the homologous sequence in Aβ (i.e. Aβ16–20). Molecular modeling suggests that association of the two homologous sequences leads to the formation of an atypical anti-parallel β-sheet structure stabilized primarily by interaction between the Lys, Leu, and COOH-terminal Phe. By screening combinatorial pentapeptide libraries exclusively composed of d-amino acids, several ligands with a general motif containing phenylalanine in the second position and leucine in the third position were identified. Ligands composed ofd-amino acids were not only capable of binding Aβ but also prevented formation of amyloid-like fibrils. These ligands are protease-resistant and may thus be useful as experimental agents against amyloid fibril formation in vivo.