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Biological Chemistry

'Prochelator' Corrals Copper On Cue

ACS Meeting News: Protease found in brains of those with Alzheimer's triggers release of potentially therapeutic copper chelator

by Amanda Yarnell
March 29, 2010 | APPEARED IN VOLUME 88, ISSUE 13

A protease found in the brains of those with Alzheimer's disease can be used to trigger the release of a chelating compound designed to mop up rogue copper, Duke University chemist Katherine J. Franz reported at this week's ACS national meeting in San Francisco.

Binding of copper to amyloid-β, a key protein player in Alzheimer's, is thought to promote both protein aggregation and the formation of damaging reactive oxygen species such as OH•. Hoping to capture and neutralize that copper, Franz and graduate student Drew S. Folk designed a "prochelator" peptide that releases a copper-chelating compound when cleaved by β-secretase, a brain enzyme closely associated with Alzheimer's (J. Am. Chem. Soc., DOI: 10.1021/ja100943r).

That protease trims off the first four amino acids of the prochelator, leaving behind a peptide with an amino terminal copper binding site that can coordinate copper in a square planar Cu(II) complex (shown). The prochelator, when processed by β-secretase in vitro, disassembles and prevents the formation of copper-induced amyloid-β aggregates. It also suppresses the copper-catalyzed formation of reactive oxygen species. Franz's team is now working to tweak the prochelator so that it might make it through the bloodstream and into the brain.

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