April 16, 1998
By Dann Hayes, (785) 864-8855
DISCOVERY BY KU RESEARCHERS COULD BE A REAL PAIN
LAWRENCE - OUCH! You've just stabbed yourself with a sewing needle while mending a hole in a shirt.
Researchers at the University of Kansas think they have found the source of the pain that travels to the brain. Now they are trying to determine how the source - a peptide called substance P - is transmitted across the blood-brain barrier, a natural barrier that surrounds the brain, which is normally closed to most substances. Peptides are molecules built of a small number of amino acids, or proteins, that are essential to life Susan M. Lunte, KU associate professor of pharmaceutical chemistry, says researchers at KU also suspect that substance will be helpful in the fight against Alzheimer's disease.
"We know that a substance called beta amyloid forms a plaque - a fibrous wall - in the brains of Alzheimer's patients," Lunte said. "Substance P inhibits the toxicity of the beta amyloid. It looks as if it actually competes with the beta amyloid."
Lunte's research is focused on analytical methodology to detect the minute amounts of substance P and other peptides present in the brain and in other parts of the body. Her research into substance P has been published in the Journal of Chromatography in 1996 and 1997.
PEPTIDES KEY TO PLACENTA RESEARCH AT KU
LAWRENCE - In the past, an expectant mother has had to suffer the pain of giving birth for fear that a pain reliever could harm her unborn child.
However, by using an artificial placenta, researchers at the University of Kansas are investigating the use of peptides in delivering drugs that treat the mother, not the fetus.
"We know what drugs do and do not cross the placenta, and there are very few that do not," said Kenneth L. Audus, professor of pharmaceutical chemistry at KU's Higuchi Biosciences Center. "We want to develop peptide drugs that work in the mother and then either fall apart near the placenta or are inactive in the fetus."
A peptide is a short chain of amino acids. Compared with conventional drugs, peptides can have extremely specific biological actions and are more potent. By using peptides, researchers believe they might also deliver certain substances to specific areas in the body.
"Morphine is an analgesic that could be a good drug to use during labor to relieve the pain," he said. "The problem is that it crosses the placental barrier. A significant side effect of the drug could be respiratory depression, which could increase the risk to the fetus."
Physicians recognize that avoiding fetal drug exposure is important during pregnancy and work with expectant mothers who require medication to prevent potential problems.
The implications of the peptide research for drug design and development could be far-reaching, Audus said.
"Think of the mother's who are on anti-epileptic drugs or the mothers on asthma medicine," he said. "Some day we may be able to identify a peptide drug that may also breakdown at the placenta. A mother could then be treated for epilepsy while the baby's health is not jeopardized by potential drug exposure."
RESEARCHERS UNLOCK DOOR TO POTENT DRUG DELIVERY SYSTEM
LAWRENCE - Researchers at the University of Kansas believe they have unlocked the door to a process of drug delivery that could improve the delivery of peptides to the brain - something that has been impossible up to now largely because of the blood-brain barrier.
Peptides - molecules built of a small number of amino acids, or proteins, that are essential to life - have shown great promise in treating various medical conditions including pain, high blood pressure and viral infections. But one of the biggest problems has been to get these types of molecules into the body where they can be most useful, such as into the brain or through the intestinal mucosa.
By manipulating the chemical structure of a peptide, Ronald T. Borchardt, Summerfield distinguished professor of pharmaceutical chemistry, and his team of researchers have strengthened its chances of delivery to specific locations in the body where the molecule can produce its therapeutic effects.
"If you are going to use peptides as drugs, you need to design them to interact with the molecular target through which they produce their therapeutic effect," Borchardt said. "You also have to design them to reach that molecular target."
By connecting the ends of the peptide by a "chemical linker," the researchers have developed a prodrug that itself is not therapeutically active but has better delivery characteristics. The U.S. Patent Office has granted a patent to KU on the methodology.
"We've taken the two ends and tied them together to form a circular molecule which has different physical and chemical properties than a normal peptide," Borchardt said. "The trick now is to make these cyclic peptides bioreversible - get them to metabolize in the body to form the therapeutically active peptide."
One of the major applications of this prodrug technology will be to make it possible to administer peptides in oral dosage forms.
"Natural peptides look like food to the human body," Borchardt said. "Mother Nature has designed natural peptides to degrade very rapidly into the amino acids. By converting a peptide into its cyclic prodrug form, we can prevent this type of metabolism, and then the peptide can successfully cross the intestinal mucosa into the blood stream."
This technology should also be useful for improving the delivery of peptides into the brain, which has been impossible in the past.
"In the past, the biomedical community has not been able to exploit the clinical potential of peptides because of their poor delivery characteristics," Borchardt said. "Perhaps the technology we have developed at KU will finally allow one or more of these peptides to become therapeutically useful drugs."
###
RSS