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Attacking Alzheimer's disease
06 May 2009
Canadian scientists have been inspired by analytical chemistry to attack Alzheimer's disease from all sides.
Chris Orvig from the University of British Columbia, Vancouver, and colleagues made multifunctional compounds to target amyloid plaque formation, a possible cause of Alzheimer's disease. Amyloid plaques are protein clusters with metal ions that accumulate between neurons in Alzheimer's patients' brains. Orvig designed his compounds to combat the protein misfolding and metal-peptide interactions involved in amyloid plaque production as well as the oxidative stress that occurs (a condition that damages cells, caused by excess free radicals). 'We aren't 100 per cent sure about the order of things and the exact interplay,' explains Orvig. 'We thought that if we could attack them all, then who knows.'
The metal-binding compounds would work against Alzheimer's in three ways on reaching the brain
Orvig's compounds are glycosylated tetrahydrosalens, metal-binding compounds protected by carbohydrates. The carbohydrates are there to stop the compounds binding to any metals before reaching their target, and to improve the compounds' solubility and uptake by the brain. Once absorbed by the brain (whose fuel source is sugar), the carbohydrates are removed by enzymes - this activates the compounds' metal-binding properties. Orvig tested his compounds in vitro and found that they prevent metal-peptide interactions by binding to the metals themselves as well as being potent antioxidants that could combat oxidative stress, a major feature of neurodegenerative diseases.
Shuang Liu, an expert in metallopharmaceuticals from Purdue University, Indiana, US, says that he would like to see results from in vivo trials but thinks that Orvig's idea is great.
Orvig says his idea was inspired by Ashley Bush's use of Clioquinol, a metal-binding compound, to treat Alzheimer's at the Mental Health Research Institute of Victoria, Australia. 'I was stunned because Clioquinol is closely related to a gravimetric reagent (compounds that bind metals strongly to allow the metals' weight to be determined) for metals, something we used in analytical chemistry in the 1960s and early 1970s,' he says.
Despite a lack of progress into research on compounds related to his tetrahydrosalens, Orvig says he knows that these compounds are able to cross the blood-brain barrier. 'We're very excited about the project,' he says.
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Link to journal article
Glycosylated tetrahydrosalens as multifunctional molecules for Alzheimer's therapy
Tim Storr, Lauren E. Scott, Meryn L. Bowen, David E. Green, Katherine H. Thompson, Harvey J. Schugar and Chris Orvig, Dalton Trans., 2009, 3034
Also of interest
Promising drug halts a metal-mediated chemical reaction in the brain
A new peptide that may be able to reverse the formation of amyloid fibrils in the brain could be the key to a cure for Alzheimer's.
Proof that peptide secondary structures can be switched by metal ions has been provided by a model based on a well known protein motif