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

We have previously shown that short peptides incorporating the sequenc e KLVFF can bind to the similar to 40-amino acid residue Alzheimer amy loid beta-peptide (A beta) and disrupt amyloid fibril formation (Tjern berg, 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 stereospecifical ly to the homologous sequence in A beta (i.e. A beta(16-20)), Molecula r modeling suggests that association of the two homologous sequences l eads to the formation of an atypical anti-parallel beta-sheet structur e stabilized primarily by interaction between the Lys, Leu, and COOH-t erminal Phe, By screening combinatorial pentapeptide libraries exclusi vely composed of D-amino acids, several ligands with a general motif c ontaining phenylalanine in the second position and leucine in the thir d position were identified, Ligands composed of D-amino acids were not only capable of binding A beta but also prevented formation of amyloi d-like fibrils, These ligands are protease-resistant and may thus be u seful as experimental agents against amyloid fibril formation in vivo.