Molecules show promising anti-prion activity
Molecules created at the University of Alberta consist of a trimesic acid scaffold at the centre, connected with three chloroquinoline groups via linkers of various lengths. These compounds show some of the best activity to date against prions, the misfolded proteins that cause mad cow disease.
By Tyler Irving
Posted October 2012
A new set of molecules developed at the University of Alberta has been shown to affect prions, the misfolded proteins that cause neurodegenerative conditions such as mad cow disease and scrapie. The finding raises hope that it may one day be possible to stop the progression of such diseases in living organisms.
The incorrectly folded, pathological form of the prion protein is called PrPSc. It has the ability to corrupt and misfold the healthy form, PrPC, which is present in most animals. PrPSc forms clusters that impair neurological function and are strongly resistant to proteases— enzymes that break down proteins. Because of this resistance, such diseases are universally fatal.
A few compounds with a moderate ability to bind to PrPSc have been reported. Chemist Frederick West is with the University of Alberta group that has been studying these compounds and trying to improve on them. “We made certain assumptions about what the business end of those inhibitors really was,” says West. “We then built molecules that consist of a series of arms coming out of a central core, each terminated with inhibitory groups, in the hopes of multiplying their effect.” The work was recently published in the journal Biomaterials.
When tested against prion-infected mouse cells in vitro, most compounds were not very effective. However, one family of molecules showed an ability to reduce the number of prions to almost zero. These consisted of three chloroquinoline groups attached to a scaffold of trimesic acid via tethers of various lengths. West cautions that much more work needs to be done in order to see if the molecule could work in vivo. He is applying for funding to learn more about how the molecules work, and whether or not they could be made more drug-like.
Photo Credit: Frederick West
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