New method may accelerate drug discovery for difficult diseases like P...(hat oxidize or reduce other molecules an...)

Interestingly, there are already links between Parkinson's and the metal manganese. Overexposure to the metal manganese can lead to parkinsonism, a Parkinson's disease-like syndrome. Also, earlier work conducted by Aaron Gitler and Melissa Geddie in the Lindquist lab found that the normal version of the gene PARK9, which can be mutated in Parkinson's disease patients, protects cells from toxic levels of manganese.

With these possible modes of action in mind, Kritzer and colleagues are now trying to figure out how the new cyclic peptides work. Using the Lindquist yeast model and a worm model of Parkinson's disease from the Caldwell lab at the University of Alabama, they confirmed that the effective cyclic peptides have the same potency as natural genes that regulate Parkinson's related cellular processes, but intercept the disease's progress at a later point. This demonstrates that these cyclic peptides act at a point in the disease process that had not been targeted by other, more traditional approaches.

According to Kritzer, who will be starting this September as an Assistant Professor of Chemistry at Tufts University, a next step in this line of research will be to determine precisely how the effective cyclic peptides affect Parkinson's disease cells by changing reduction or oxidation within the cell, binding to metal molecules, or perhaps another mechanism. In addition, more potent structures may be possible, so the cyclic peptides' known structure can be used as a starting point for more libraries which may produce even more effective versions.

Lindquist also says the technique is not limited to just yeast or just Parkinson's disease. "There's absolutely no reason we couldn't apply the same process to mammalian cells. And it should be applicable to all sorts of diseases that are modeled in yeast," she says. "In fact, that's some of the stuff we've st
'/>"/>