Working with Harvard’s Laboratory for Drug Discovery in Neurodegeneration, Abraham’s team screened 77,000 molecules that they thought might affect APP dimerization. They focused on small molecules because large ones don’t easily cross the blood–brain barrier.
“If you want to treat brain disease, you need small molecules,” says Abraham. “If you use large molecules like antibodies, only a very small percentage get into the brain, and they can have huge effects on the rest of the body.”
The drug screen turned up one significant hit. Abraham showed the molecule to her colleague John Porco, professor of chemistry and director of Boston University’s Center for Molecular Discovery. Porco identified the molecule almost immediately: It was a kinase inhibitor. These block the action of enzymes called kinases, which are common in many cellular processes
“This was the big eureka moment,” says Abraham. “Once we knew what the molecule was doing, we could search to see what kinase it inhibits and better understand the mechanism.”
Further work found that the molecule was acting on a kinase in a larger cell-signaling complex. Abraham hopes that more research will find the enzyme that acts directly on APP. “That would be the target,” she says.
Her team is now looking for similar molecules that may work even better, and for other molecules in the pathway that may also become drug targets. The ultimate goal, says Abraham, is an effective drug where none now exists.
“Right now there is nothing,” says Abraham. “We must find something new.”
Featured Image Credit: Dave King/Flickr
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