Sep 1 2005
Chemists at the University of Arizona have developed modified versions of naturally occurring peptide hormones that could be key to novel treatments of a variety of diseases, including eating disorders (anorexia, obesity), diabetes, sexual dysfunction and skin cancer.
Victor Hruby, who is a Regents' Professor at the department of chemistry in UA's College of Science and a member of the Drug Discovery Initiative at UA's BIO5 Institute, will talk about the biological roles of peptide hormones and possible applications for designed peptides at the 230th American Chemical Society National Meeting in Washington, DC, on Aug 31, 2005.
Melanotropins are peptide hormones produced in different parts of the body. They play key roles in regulating many biological functions, e.g. eating behavior and metabolism, stress reactions, skin pigmentation and sexual behavior. In the body, melanotropins exert their various functions by binding to specific cellular receptor molecules called melanocortin receptors. To date, scientists have identified five melanocortin receptors (named MC1R through MC5R), all of which differ slightly from each other regarding chemical structure, binding affinity for certain peptides and biological function.
The UA team, led by Hruby, has figured out ways to modify these molecules in the laboratory so they offer improved properties over their natural counterparts. Melanotropins in the body tend to degrade quickly and have overlapping binding specifities (i.e. they bind to different melanocortin receptors). Typically, a given type of melanocortin receptor has a preference for a certain melanotropin, but it can bind to various others, playing a major role in a biological function and a participating role in others.
"We discovered that if we alter the chemical structure of the ligands in a slight but very precise way, they become 100 times more selective or 100 times more potent," said Hruby.
In contrast to the melanotropins occurring in the body, which tend to degrade quickly, sometimes within seconds, the artificial ligands are more stable. This is a crucial prerequisite for any drug that is administered peripherally and then travels through the intestinal tract and/or the blood stream.
Scientists hope that melanotropin-based drugs can overcome certain disadvantages of drugs that are currently available.
"Patients would have to take less amounts of a melanotropin-based drug and experience fewer side effects," Hruby said.
Hruby's team also managed to modify ligands so that they can cross the blood-brain barrier - an obstacle that prevents most substances circulating in the bloodstream from trespassing into the brain tissue. Since many melanocortin receptors are located in the brain, however, any drug that is supposed to act on these receptors has to cross the barrier.
Ligands developed by the UA scientists include a host of promising drug candidates. Some could be used as drugs to dampen appetite, others to restore erectile function and still others have been shown to promote tanning of the skin.
"People with fair skin complexion who are at greater risk from sunburn could benefit from a darker skin color that protects them from the sun in a natural way," said Hruby.
The UA scientists use structural design methods including structure-activity relationship analysis (SAR) to tailor compounds with the desired properties.
"We use computer-aided drug design to see what sorts of structures we can change without altering the basic structural features that are important for the molecule to exert its function," explained Hruby. His team uses in-vitro systems such as transfected cell lines to study the effect of the candidates on the cells' signal transduction mechanisms.
When given to animals in laboratory studies, some of the modified peptide ligands caused the animals to become less interested in feeding.
"In other words, you lose the motivation to eat," said Hruby. However, he was quick to add a caveat: If there will ever be a drug like that, it will be one factor among others - such as exercise and a change in lifestyle.
"There will be no magic bullet," Hruby said. "Just taking these pills while sitting on the couch and eating a TV dinner won't make you go from 300 pounds to 150."
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