Designed Peptides: Candidates For The Treatment Of Cancer, Sexual Dysfunction, Eating Disorders

Victor Hruby, who is a Regents' Professor at the department ofchemistry in UA's College of Science and a member of the Drug DiscoveryInitiative at UA's BIO5 Institute, will talk about the biological rolesof peptide hormones and possible applications for designed peptides atthe 230th American Chemical Society National Meeting in Washington, DC,on Aug 31, 2005.

Melanotropins are peptide hormones produced in different partsof the body. They play key roles in regulating many biologicalfunctions, e.g. eating behavior and metabolism, stress reactions, skinpigmentation and sexual behavior. In the body, melanotropins exerttheir various functions by binding to specific cellular receptormolecules called melanocortin receptors. To date, scientists haveidentified five melanocortin receptors (named MC1R through MC5R), allof 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 modifythese molecules in the laboratory so they offer improved propertiesover their natural counterparts. Melanotropins in the body tend todegrade quickly and have overlapping binding specifities (i.e. theybind to different melanocortin receptors). Typically, a given type ofmelanocortin receptor has a preference for a certain melanotropin, butit can bind to various others, playing a major role in a biologicalfunction and a participating role in others.

"We discovered that if we alter the chemical structure of theligands in a slight but very precise way, they become 100 times moreselective or 100 times more potent," said Hruby.

In contrast to the melanotropins occurring in the body, whichtend to degrade quickly, sometimes within seconds, the artificialligands are more stable. This is a crucial prerequisite for any drugthat is administered peripherally and then travels through theintestinal 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 cancross the blood-brain barrier - an obstacle that prevents mostsubstances circulating in the bloodstream from trespassing into thebrain tissue. Since many melanocortin receptors are located in thebrain, however, any drug that is supposed to act on these receptors hasto cross the barrier.

Ligands developed by the UA scientists include a host ofpromising drug candidates. Some could be used as drugs to dampenappetite, others to restore erectile function and still others havebeen shown to promote tanning of the skin.

"People with fair skin complexion who are at greater risk fromsunburn could benefit from a darker skin color that protects them fromthe sun in a natural way," said Hruby.

The UA scientists use structural design methods includingstructure-activity relationship analysis (SAR) to tailor compounds withthe desired properties.

"We use computer-aided drug design to see what sorts ofstructures we can change without altering the basic structural featuresthat are important for the molecule to exert its function," explainedHruby. His team uses in-vitro systems such as transfected cell lines tostudy the effect of the candidates on the cells' signal transductionmechanisms.

When given to animals in laboratory studies, some of themodified peptide ligands caused the animals to become less interestedin 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 druglike that, it will be one factor among others - such as exercise and achange in lifestyle.

"There will be no magic bullet," Hruby said. "Just takingthese pills while sitting on the couch and eating a TV dinner won'tmake you go from 300 pounds to 150."

This research was supported by grants from: United States Public Health Service, NIH.

Information on the web:
Victor Hruby: http://bio5.arizona.edu/bio5/database.php?cmd=fac&faculty_id=2722
BIO5 Institute: http://bio5.org
The University of Arizona: www.arizona.edu

Reference:
Melanotropin ligands for the hMC4Rs: Multiple biological activities!One receptor? The challenge! Victor J. Hruby, Minying Cai, Jinfa Ying,Alexander Mayorov, Ravil Petrov, James Cain, Chad Park and Dev Trivedi,Department of Chemistry, University of Arizona, 1306 E. UniversityBlvd, P.O. Box 210041, Tucson, AZ 85721, USA