Controlling amyloid beta-peptide fibril formation with protease-stable ligands.
We have previously shown that short peptides incorporating the sequence KLVFF can bind to the approximately 40amino acid residue Alzheimer amyloid beta-peptide (Abeta) and disrupt amyloid fibril formation (Tjernberg, L. O., Näslund, J., Lindqvist, F., Johansson, J., Karlström, 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 Abeta (i.e. Abeta16-20). Molecular modeling suggests that association of the two homologous sequences leads to the formation of an atypical anti-parallel beta-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 of D-amino acids were not only capable of binding Abeta 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.
Tjernberg
L O
LO
Laboratory of Biochemistry and Molecular Pharmacology, Section of Drug Dependence Research, Department of Clinical Neuroscience, Karolinska Hospital, S-171 76 Stockholm, Sweden.
Lilliehöök
C
C
Callaway
D J
DJ
Näslund
J
J
Hahne
S
S
Thyberg
J
J
Terenius
L
L
Nordstedt
C
C
D000596:Amino Acids / Q000032:analysis; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001665:Binding Sites; D010450:Endopeptidases / Q000378:metabolism*; D008958:Models, Molecular; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D000596:Amino Acids; D016229:Amyloid beta-Peptides; C106100:LBMP1620 protein, synthetic; D019151:Peptide Library; D010455:Peptides; D010450:Endopeptidases