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Biological Chemistry

Tweezing Apart Amyloids

Therapeutics: Small molecule sticks to lysine to unglue protein aggregates

by Erika Gebel
October 3, 2011 | A version of this story appeared in Volume 89, Issue 40

A clawlike molecule that can unravel the aberrant protein snarls behind diseases such as Alzheimer’s and Parkinson’s may serve as the basis for a new strategy to treat a broad range of protein-misfolding diseases (J. Am. Chem. Soc., DOI: 10.1021/ja206279b).

The protein clumps associated with these diseases are called amyloids. They form when normal proteins in the cell unfold and then stick together in aggregates that can damage cells. Previous research on amyloids suggests the amino acid lysine in proteins acts as an amyloid glue. With a long alkane chain and a terminal amine group, lysine can associate with any complementary surface—an amino acid, other small molecules, proteins—through both hydrophobic and electrostatic interactions, two forces that drive protein aggregation.

For 10 years, Gal Bitan of the University of California, Los Angeles, has been studying amyloid-β, the protein associated with Alzheimer’s disease. When he read about a molecule called CLR01 that specifically binds lysine, he formed a hypothesis—disrupting lysine’s interactions would unglue amyloids—and immediately wanted to test it using CLR01. This lysine grabber is a molecular tweezer, a class of Pac-Man-shaped molecules designed to engulf a particular target. But CLR01 binds to lysine weakly enough that it won’t interfere with the work of healthy proteins, Bitan says.

Bitan and his team first tested the tweezer’s effect on amyloid-β. They mixed CLR01 with the protein and monitored the formation of amyloids using a dye that fluoresces upon binding to a common structural motif in amyloids. The fluorescence data revealed that CLR01 completely shuts down amyloid formation in solution. In addition, they showed that CLR01 breaks down previously formed amyloids.

Next they determined whether the tweezer could save cells from amyloid-β aggregates, which usually kill cultured cells. The researchers first primed the proteins to aggregate by mixing them in an aggregate-promoting solution, and then they added the proteins to the cells with or without the molecular tweezer. At a concentration about two orders of magnitude lower than what could kill cells, the lysine grabber completely prevented cell death from the aggregates.

Amyloid-β is just one of several proteins that aggregate into noxious clumps; each amyloid disease has its own signature protein. When Bitan tested CLR01 against nine amyloid-forming proteins, using a combination of the fluorescence and cell death tests, CLR01 inhibited the harmful aggregation of all but one. The exception was a prion, the kind of protein responsible for diseases such as Creutzfeldt-Jakob disease. Bitan says this prion is an unusual case, because they tested only a fragment of it.

James Shorter of the University of Pennsylvania calls the study “an important proof-of-principle experiment.” He is surprised by the ability of CLR01 to wreak havoc on so many different types of amyloids. “I think the broad specificity is really the interesting part of the study,” he says.



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