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New Therapeutic Leads for Cachexia and Anorexia: Design of a Small Protein that Significantly Enhances Mammalian Feeding
University of California System: University of California, Santa Cruz
posted on 10/20/2011
The agouti-related protein (AgRP) is produced in the brain and is a potent appetite stimulant. The normal 50 amino acid polypeptide is produced in the hypothalamus and binds with high affinity to the melanocortin 3 and 4 receptors (MC3R and MC4R). Along with alpha-melanocyte stimulating hormone (apha-MSH) and neuropeptide Y, AgRP plays a central role in the regulation of mammalian feeding and metabolism. From intracerebroventricular (ICV) injection studies, AgRP is well documented to enhance feeding for one to two days following a single injection, and is probably longer acting than any other known hormone or drug.
Suggested Uses
UCSC researchers believe that these proteins will ultimately be of value in treating extreme cases of eating disorders such as anorexia or cachexia. Furthermore, the principles used in the design of these proteins may find value in the development of therapeutics.
Advantages
The animals increase their body weight by 15% in a one week period, compared to 5% in animals treated with wild type AgRP.
Detailed Description
UCSC researchers have previously isolated the specific region of AgRP that is required to bind to the MC receptors. New studies show regions adjacent to those that make receptor contact are rich with positive charges, and while they do not influence receptor affinity, they’re critical for AgRP’s long acting activity. UCSC researchers have now designed non-natural proteins where they’ve selectively enhanced certain sequence and charge characteristics and are able to greatly extend the time over which a single AgRP injection stimulates feeding. Normally, from ICV injections in rats, AgRP stimulates feeding over a 24 – 72 hour period, one to three days. UCSC researchers show that the newly designed protein stimulates feeding for six days. Moreover, the cumulative food intake stimulated by UCSC’s designed AgRP is approximately double that of control over the lifetime of the experiment. The animals increase their body weight by 15% in a one week period, compared to 5% in animals treated with wild type AgRP.
File Number: 22013
Disease: Women's Health
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