Where are the new drugs?  pg. 4

“I see it as a really challenging time. But mostly I see it as a very exciting time.”

Pie in the sky

Another potential source of new drugs: compounds that interact with G-proteins.

G-proteins are intracellular molecular switches, involved in nearly every physiological—and presumably, pathological—process. They translate and transmit signals from the receptor to the “response machinery” deep inside the cell.

Here’s how they work:

"There are real benefits… to the scientists doing the research. Even if only 10 percent of these compounds were picked up by industry, the scientific programs would benefit from having potent new tools to probe the biology in cells and even in animals more deeply, leading to new discoveries."
Heidi Hamm, Ph.D., Earl W. Sutherland Jr. Professor and Chair of the Department of Pharmacology at Vanderbilt
Photo by Dean Dixon
When a neurotransmitter or hormone binds to its G protein-coupled receptor on the surface of a cell, the receptor, in turn, activates G proteins that bind to it inside the cell. The proteins actually split into two active parts—alpha subunits and beta/gamma subunits—both of which can stimulate independent signaling pathways.

Drugs that target GPCRs are rather blunt instruments; they can trigger far-ranging side effects. Is it possible to develop drugs that can be delivered—with “nano-surgical” precision—to the G protein of a specific receptor inside a particular type of cell? Could that achieve the therapeutic manipulation of a unique signaling pathway without affecting physiology anywhere else?

That prospect has tantalized Heidi Hamm, Ph.D., for more than two decades. But until recently the idea was, as Hamm puts it, “total pie in the sky.”

In 1993, Hamm helped solve the structure of the alpha subunit with the late Paul Sigler, M.D., Ph.D., and his colleagues at Yale.

More recently, she and colleagues at the University of Illinois at Chicago and the University of Wisconsin-Madison showed how the beta/gamma subunit of an inhibitory G protein controls the release of neurotransmitters and hormones. It prevents vesicles containing these chemical messengers from fusing to the cell membrane and spilling their contents outside the cell.

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