March 2, 1999--Many biological processes are triggered by the interaction, or binding, of molecules. So important is this motif in nature that numerous strategies have evolved to ensure the proper union of molecules. HHMI investigator Gerald Crabtree and colleagues at Stanford University have borrowed a trick used by microbes and cells in the immune system to engineer drug molecules that bind to their targets more effectively.

More importantly, says Crabtree, the approach also offers a new solution to the frustrating problem of developing small molecule drugs that can prevent two large proteins from binding to one another.

"Small molecules have not been very successful at inhibiting protein-protein interactions because the protein surfaces are huge," said Crabtree. "They are like molecular football fields, and using a small molecule to prevent these surfaces from coming together is like putting a pea down on a football field."

Crabtree and Stanford colleagues Roger Briesewitz, Gregory Ray and Thomas Wandless leveled the playing field by increasing the size of the small molecule inhibitor. They did this by chemically attaching the inhibitor to another small linker molecule that binds tightly to a much bigger "presenting" protein that exists naturally in the human body.

In essence, the combination of small drug molecule, linker and big protein allows the drug candidate to borrow the huge surface area of the presenting protein, making it appear to its target as if it is much bigger and stickier.

"Using a presenting protein is like bringing in a molecular wrecking ball instead of a pea," says Crabtree, because you "create a molecule with so much surface area that it now has a chance of out-competing the normal protein-protein interaction that you are trying to disrupt."

Crabtree, who has spent more than a decade deciphering the signals that turn on the
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
2-Mar-1999