Test providing new pathway for identifying obesity, diabetes drugs developed

Researchers at The Scripps Research Institute have developed a new molecular test that will allow researchers to look for potential drugs targeting a human metabolic enzyme believed to stimulate the appetite and play a role in diabetes.
 
The new test, which the scientists call a simple assay, will allow researchers to look through hundreds of thousands of compounds for those that have potential to block the action of an enzyme known as ghrelin O-acyltransferase (GOAT).

"There hasn't been a simple screen until now," says Kim D. Janda, director of The Worm Institute for Research and Medicine at Scripps Research.

Ghrelin, a small peptide hormone that is mainly produced in the stomach, signals hunger, typically before meals.

Ghrelin has been associated with Prader-Willi syndrome, a common genetic cause of childhood obesity, in which patients have exceptionally high ghrelin levels.

The biology of ghrelin is quite intricate. For ghrelin to impact the body's metabolism, it must move from the stomach to the brain, where it acts on neurons.

 GOAT acts as a "passport" check point station for the processing of 'pro-ghrelin.'

"Without GOAT's modification of 'pro-ghrelin,' ghrelin's entry into the brain, and thus its medicinal implications, are nullified," said Janda, a research associate.

 "That's why GOAT has been coveted as a promising therapeutic target for obesity and diabetes," he added.

In developing their new approach, the team was inspired by enzyme immunoassay strategies commonly used in biology, chemistry, and medicine, and by "click chemistry," a concept developed at Scripps Research.

Because the amount of ghrelin modified by GOAT is minute, the scientists also used the principle of multi-turnover signal amplification for accurate detection.

In the end, the team succeeded in designing and creating the new technology-which they call "catalytic assay using enzyme-linked click chemistry assay" (cat-ELCCA).

"This new assay technology is both highly sensitive and reproducible," noted Janda, "making it an excellent assay for high-throughput screening."

The finding was published in an advance online early edition of the journal Angewandte Chemie on September 15, 2010.