New strategy for the generation of specific D-peptide amyloid inhibitors.
The conversion of a soluble protein into beta-sheet-rich oligomeric structures and further fiber formation are critical steps in the pathogenesis of the group of human diseases known as amyloidoses. Drugs that interfere with this process may thus be able to prevent and/or cure these diseases. Recent results have shown that short amino acid stretches can provide most of the driving force needed to trigger amyloid formation of a protein. These evidence suggest that compounds that specifically bind to peptides synthesized upon the sequence of such amyloidogenic protein stretches might also be able to inhibit amyloid formation of the corresponding full-length protein and, likely, amyloid-induced cytotoxicity as well. Here we present a general strategy to obtain d-peptides that specifically interact with protein amyloid stretches. The screening of a d-peptide combinatorial library for inhibitors of an amyloidogenic peptide designed de novo has allowed us to extract a set of empirical rules for the design of d-peptide inhibitors of any six-residue amyloidogenic stretch. d-peptides generated on these bases prevent amyloid formation and disassemble preformed fibrils of different amyloid hexapeptides identified in human amyloid proteins. In addition, they are also specific for their target sequence. The d-peptide designed here for the Alzheimer's Abeta(1-42) peptide not only inhibits and disassembles amyloid material but also reduces Abeta(1-42) amyloid-induced cytotoxicity in cell culture.
Esteras-Chopo
Alexandra
A
Computational and Structural Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Baden-Württemberg, Germany.
Pastor
M Teresa
MT
Serrano
Luis
L
López de la Paz
Manuela
M
D000595:Amino Acid Sequence; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000648:ultrastructure; D000686:Amyloidosis / Q000517:prevention & control; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D016716:PC12 Cells; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019151:Peptide Library; D017433:Protein Structure, Secondary; D051381:Rats
D000682:Amyloid; D010446:Peptide Fragments; D019151:Peptide Library