Rationally designed dehydroalanine (DeltaAla)-containing peptides inhibit amyloid-beta (Abeta) peptide aggregation.
Among the pathological hallmarks of Alzheimer's disease (AD) is the deposition of amyloid-beta (Abeta) peptides, primarily Abeta (1-40) and Abeta (1-42), in the brain as senile plaques. A large body of evidence suggests that cognitive decline and dementia in AD patients arise from the formation of various aggregated forms of Abeta, including oligomers, protofibrils and fibrils. Hence, there is increasing interest in designing molecular agents that can impede the aggregation process and that can lead to the development of therapeutically viable compounds. Here, we demonstrate the ability of the specifically designed alpha,beta-dehydroalanine (DeltaAla)-containing peptides P1 (K-L-V-F-DeltaA-I-DeltaA) and P2 (K-F-DeltaA-DeltaA-DeltaA-F) to inhibit Abeta (1-42) aggregation. The mechanism of interaction of the two peptides with Abeta (1-42) seemed to be different and distinct. Overall, the data reveal a novel application of DeltaAla-containing peptides as tools to disrupt Abeta aggregation that may lead to the development of anti-amyloid therapies not only for AD but also for many other protein misfolding diseases. (c) 2009 Wiley Periodicals, Inc. Biopolymers 91: 456-465, 2009.
Rangachari
Vijayaraghavan
V
Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA. vijay.rangachari@usm.edu
Davey
Zachary S
ZS
Healy
Brent
B
Moore
Brenda D
BD
Sonoda
Leilani K
LK
Cusack
Bernadette
B
Maharvi
Ghulam M
GM
Fauq
Abdul H
AH
Rosenberry
Terrone L
TL
D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics; D015195:Drug Design; D013058:Mass Spectrometry; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics
D016229:Amyloid beta-Peptides; D009842:Oligopeptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C542105:lysyl-leucyl-valyl-phenylalanyl-delta-alanyl-isoleucyl-delta-alanine; C542106:lysyl-phenylalanyl-delta-alanyl-delta-alanyl-delta-alanyl-phenylalanine; C015102:dehydroalanine; D000409:Alanine