Platinum-based inhibitors of amyloid-beta as therapeutic agents for Alzheimer's disease.
Amelyoid-beta peptide (Abeta) is a major causative agent responsible for Alzheimer's disease (AD). Abeta contains a high affinity metal binding site that modulates peptide aggregation and toxicity. Therefore, identifying molecules targeting this site represents a valid therapeutic strategy. To test this hypothesis, a range of L-PtCl(2) (L = 1,10-phenanthroline derivatives) complexes were examined and shown to bind to Abeta, inhibit neurotoxicity and rescue Abeta-induced synaptotoxicity in mouse hippocampal slices. Coordination of the complexes to Abeta altered the chemical properties of the peptide inhibiting amyloid formation and the generation of reactive oxygen species. In comparison, the classic anticancer drug cisplatin did not affect any of the biochemical and cellular effects of Abeta. This implies that the planar aromatic 1,10-phenanthroline ligands L confer some specificity for Abeta onto the platinum complexes. The potent effect of the L-PtCl(2) complexes identifies this class of compounds as therapeutic agents for AD.
Barnham
Kevin J
KJ
Department of Pathology, University of Melbourne, Parkville, Victoria, 3010, Australia. kbarnham@unimelb.edu.au
Kenche
Vijaya B
VB
Ciccotosto
Giuseppe D
GD
Smith
David P
DP
Tew
Deborah J
DJ
Liu
Xiang
X
Perez
Keyla
K
Cranston
Greg A
GA
Johanssen
Timothy J
TJ
Volitakis
Irene
I
Bush
Ashley I
AI
Masters
Colin L
CL
White
Anthony R
AR
Smith
Jeffrey P
JP
Cherny
Robert A
RA
Cappai
Roberto
R
D000544:Alzheimer Disease / Q000188:drug therapy*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D002942:Circular Dichroism; D006861:Hydrogen Peroxide / Q000378:metabolism; D020128:Inhibitory Concentration 50; D017774:Long-Term Potentiation / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000633:toxicity; D010084:Oxidation-Reduction / Q000187:drug effects; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017356:Synchrotrons
D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010984:Platinum; D006861:Hydrogen Peroxide