Conformational restriction via cyclization in beta-amyloid peptide Abeta(1-28) leads to an inhibitor of Abeta(1-28) amyloidogenesis and cytotoxicity.
The aggregation process of beta-amyloid peptide Abeta into amyloid is strongly associated with the pathology of Alzheimer's disease (AD). Aggregation may involve a transition of an alpha helix in Abeta(1-28) into beta sheets and interactions between residues 18-20 of the "Abeta amyloid core." We applied an i, i+4 cyclic conformational constraint to the Abeta amyloid core and devised side chain-to-side chain lactam-bridged cyclo(17, 21)-[Lys(17), Asp(21)]Abeta(1-28). In contrast to Abeta(1-28) and [Lys(17), Asp(21)]Abeta(1-28), cyclo(17, 21)-[Lys(17), Asp(21)]Abeta(1-28) was not able to form beta sheets and cytotoxic amyloid aggregates. Cyclo(17, 21)-[Lys(17), Asp(21)]Abeta(1-28) was able to interact with Abeta(1-28) and to inhibit amyloid formation and cytotoxicity. Cyclo(17, 21)-[Lys(17), Asp(21)]Abeta(1-28) also interacted with Abeta(1-40) and interfered with its amyloidogenesis. Cyclo(17, 21)-[Lys(17), Asp(21)]Abeta(1-28) or similarly constrained Abeta sequences may find therapeutic and diagnostic applications in AD.
Kapurniotu
Aphrodite
A
Laboratory of Bioorganic and Medicinal Chemistry, Institute of Biochemistry, University Hospital of the RWTH Aachen, D-52074 Aachen, Germany. akapurniotu@ukaachen.de
Buck
Andreas
A
Weber
Marco
M
Schmauder
Anke
A
Hirsch
Thomas
T
Bernhagen
Jürgen
J
Tatarek-Nossol
Marianna
M
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000633:toxicity; D052160:Benzothiazoles; D002470:Cell Survival / Q000187:drug effects; D002850:Chromatography, Gel; D002942:Circular Dichroism; D003224:Congo Red; D003500:Cyclization; D015195:Drug Design; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000633:toxicity; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D010446:Peptide Fragments; D013778:Tetrazolium Salts; D013844:Thiazoles; C084358:amyloid beta-protein (1-28); C009462:thioflavin T; D003224:Congo Red; C022616:thiazolyl blue