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Mechanism found for destruction of key allergy-inducing complexes, Stanford researchers say
Date:10/28/2012

ration of the two groups resulted in the characterization of DARPin E2-79, an inhibitor that goes beyond mere blockade to actively disassemble the IgE-FcR power couple.

Jardetzky's group solved E2-79'S structure and used this information to model its interaction with the IgE-FcR pair. Then, using sensitive biochemical techniques that detect step-by-step binding interactions between molecules, the teams were able to tease out the mechanism that the inhibitor uses to break the IgE-FcR bond.

The researchers found that E2-79 hastens the separation of the two molecules by taking advantage of a moment of weakness in the relationship between IgE and FcR. IgE maintains its interaction with FcR using two contact points, and occasionally one of these points releases while the other one keeps the pair together. Normally this brief looseness isn't enough to separate the couple, but E2-79 can swoop into the small space between them, effectively driving the couple apart.

While E2-79 is the first molecule to display these IgE stripping characteristics, Jardetzky hopes that this work will stimulate the discovery of smaller compounds capable of working even more efficiently. Drug developers generally expect large macromolecules like E2-79 to be less potent than small molecule inhibitors and unlikely to be able to disrupt complexes, so the fact that E2-79 worked so well was a surprise. Small molecules are more amenable to oral administration, and are easier and cheaper to manufacture than large macromolecules. "Now we're in the hunt for a small molecule that could have this kind of activity. That would be the real hit," said Jardetzky.

The discovery of E2-79's mechanism of IgE inhibition could lead to rapid discoveries from other labs as well. Now that scientists know what mechanism to look for, they may be inspired to dig back through freezers full of IgE inhibitors that were identified years ago, said Jardetzky. In the light of techniques describ
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Contact: Rosanne Spector
manishma@stanford.edu
650-725-5374
Stanford University Medical Center
Source:Eurekalert

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