Prions are shape-shifting proteins that act like germs, infecting healthy tissue and causing havoc in the body. Prions pass on, or infect, by converting normally folded molecules of the same protein into abnormally structured clumps called amyloid. The changed structure is extremely stable and accumulates in infected tissue, causing tissue damage and cell death, often leading to devastating disorders in the brain, such as ‘mad cow’ disease. This extreme stability and the ability to shift into multiple different shapes or ‘strains’ make prions exceptionally difficult drug targets.
Yeast prions. Credit: James Shorter, PhD.
In a paper published in Nature Chemical Biology, researchers found that yeast prions were able to evade a small-molecule inhibitor by shifting into a novel drug-resistant shape that does not usually appear. However, by combining two small molecules, prions could no longer escape and were eradicated.
“We were very surprised to find that the prion could change into a brand new shape to evade what we had anticipated to be a very potent small molecule inhibitor. However, by combining two different inhibitors we were able to hit multiple prion strains.” says senior author James Shorter, PhD, assistant professor of Biochemistry and Biophysics at the Perelman School of Medicine.
These findings provide proof-of-principle that small molecule combinations can counter strains of amyloid, which likely plays an important role in other fatal neurodegenerative disorders, including Alzheimer’s and Huntington’s disease.
“When used together their effect was synergistic, because the two small molecules work in different ways to break up the prions. We suspect that small molecule cocktails that safely eradicate complete strain repertoires can be found for various neurodegenerative disorders.” says Shorter.
This research was done in collaboration with Martin Duennwald at the Boston Biomedical Research Institute.