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June 08, 2007

Inhibiting a single protein lengthen fruit fries life by a third

From physorg, Fruit flies with a single blocked protein receptor saw their lives extended by a third, with no apparent side effects.

They also used a highly parallelized and combinatorial (trillions of tests) method to find the effective binding molecule. This can be part of methodologies to interfere and control the metabolism of people.


This method could have application for gerontology, engineering and geriatrics.

“First, it demonstrates that a single inhibitor can dramatically alter lifespan, a very complex trait. It is remarkable that you can alter it with a single genetic change.

“We don’t really need to make fruit flies live longer, but if we understand how to do this, our approach may have direct application to higher organisms, such as ourselves.”

Secondly, Roberts said, the method used by his research group to make the inhibiting proteins “opens the possibility of developing a lot of new therapeutics [drugs].”

Receptors are proteins that transmit signals across a cell membrane. In the fruit fly, Roberts and his team manufactured short proteins that blocked a receptor involved in fruit fly aging, as previously demonstrated by co-author Seymour Benzer of Caltech.

The same blocking strategy should work in all such receptors, known as class B GPCRs (for G protein-coupled receptors). Many GPCRs figure prominently in disease as well as in normal development, Roberts said.

“It is the most targeted family of receptors” by drug manufacturers, Roberts said, estimating that a quarter of all pharmaceuticals focus on GPCRs.

“This approach should be generally applicable.”

And generally powerful, given that GPCRs are notoriously unstable and difficult to work with. The Roberts group went around the problem by cutting off the unstable part of the receptor and running experiments only on the part of the receptor that sticks out of the cell.

“Essentially, we developed a way to do PCR on proteins,” Roberts said.

The use of RNA-peptide fusions allowed the easy creation and multiplication of randomly generated peptides. Roberts termed this approach “Irrational Design.”

In the new study, Roberts and his group literally threw trillions of peptides at the receptor and saved the ones that stuck.

“We let the molecules themselves decide if they bind, rather than trying to design them rationally,” he said.

After multiple cycles, the researchers had a group of peptides that stuck to the receptor and not to any other protein.

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