From Snakes and Frogs, Possible New Treatments for Digestive Disease

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FROM SNAKES AND FROGS, POSSIBLE NEW TREATMENTS FOR DIGESTIVE DISEASE

College of Medicine Researchers Discover Naturally Occurring Human Proteins That Regulate Intestinal Muscles

Irvine, Calif., April 17, 2001 -- A previously unknown class of proteins chemically related to snake venom and frog skin secretions may lead to the development of new treatments for a range of stubborn digestive disorders, a UC Irvine College of Medicine research team has found.

The findings, reported in the April issue of Molecular Pharmacology, mark the discovery of two naturally occurring human proteins, which the researchers have named prokineticins ("pro-kin-ETT-eh-sins"). How the proteins were discovered is a tale of biological detective work mixing traditional comparisons with other animals and the latest computerized informatics research.

Qun-Yong Zhou, assistant professor of pharmacology, and his colleagues found that the prokineticin proteins controlled movement of muscles in the intestines of guinea pigs. These muscles regulate the movement of food through the digestive system.

The proteins could hold the key to understanding how digestion is regulated and eventually could result in better treatments for disorders like irritable bowel syndrome, gastric reflux disease, chronic constipation and digestive complications of diabetes. Currently, there are no consistently effective treatments for these disorders, which affect more than 10 percent of Americans.

"We started by looking for proteins similar to proteins in frog skin secretions (which are poisonous in certain species) and in snake venom because they cause intestinal muscle contractions in those animals," Zhou said. "We then searched databases for chemicals that were similar in structure and function for mammals. We found what we believe may result in more effective treatments for a number of digestive diseases and could even help reduce vomiting and other gastrointestinal side effects of cancer chemotherapy."

The researchers mined the chemicals by combining sophisticated genome database searching with laboratory bench work to find the chemicals most likely to act like the snake venom and frog secretions.

"By testing the effects of the chemicals on intestinal muscles, we found what we called prokineticins. These proteins appear to control intestinal muscles and could be used to form treatments for diseases caused by abnormal muscle contractions in the gut," Zhou said.

Very small doses of the protein caused strong muscle contractions in the gut, especially in the small intestine. The proteins did not affect the same type of muscles in the heart, arteries or lungs, indicating that the prokineticins played an exclusive role in regulating intestinal muscles. The researchers found two prokineticins that are chemically similar.

In addition, the researchers found a site that may be a receptor on the surface of intestinal muscle cells. This site had a chemical structure that may be able to bind with the proteins in the laboratory, indicating that the prokineticins could control muscle cells' movement through a receptor.

The smooth digestion of food, absorption of nutrients and evacuation of waste are heavily dependent on muscle movement in the gastrointestinal tract. This movement is regulated by a host of proteins, including neurotransmitters, hormones and other chemicals. Any disruption in the regulation of this muscle movement can result in disease.

"We still need to map out exactly how these proteins work and see if they work the same way in humans before we begin to develop treatments for intestinal disorders," Zhou said.

The researchers now are working on further characterizing the potential receptors which could be the site at which the prokineticins control muscle movement. Understanding how these receptors and proteins work could be the key to developing new treatments for gastrointestinal disorders.

Zhou's colleagues on the study included graduate students Ming Li and Clayton M. Bullock and professors Daniel J. Knauer and Frederick J. Ehlert, all of UCI.

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Contact:Andrew Porterfield(949) 824.3969[email protected]

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