How to design a better drug to treat cystic fibrosis
Sep 4, 2005, 08:30, Reviewed by: Dr.
|"The chemical mechanisms directing chloride binding and transport are poorly understood. The mechanisms determining how sodium, potassium and calcium get across are much better known. We're trying to find out how chloride actually gets across so we will then be able to manipulate both the transport rates and selectivity."
John Tomich, a Kansas State University professor of biochemistry, spends much of his day thinking about how to design a better drug to treat cystic fibrosis.
A chronic and progressive disease, cystic fibrosis is usually diagnosed in childhood. It causes mucus to become thick, dry and sticky. The mucus builds up and clogs passages in the lungs, pancreas and other organs in the body.
There is no cure for cystic fibrosis. Management of the disease varies from person to person and generally focuses on treating respiratory and digestive problems to prevent infection and other complications. Treatment usually involves a combination of medications and home treatment methods, such as respiratory and nutritional therapies.
Tomich, along with colleagues Takeo Iwamoto, a K-State research assistant professor, and Shawnalea J. Frazier, senior in biochemistry, Haysville, have been working to understand how ions travel across cell membranes, specifically the anion part of sodium chloride.
Tomich presented a paper on the trios' findings, "Assessing The Contributions of H-Bonding Donors to Permeation Rates and Selectivity in Self-Assembling Peptides that Form Chloride Selective Pores," Aug. 28 at the Membrane Active, Synthetic Organic Compounds Symposium of the American Chemical Society's national meeting and exposition in Washington, D.C.
"What's kind of an honor about this is we were one of the few, purely biochemical research groups who are presenting in this symposium," Tomich said. "This is a section organized by organic chemists."
Tomich and his collaborators have used a series of single and double amino acid substitutions to modulate the activity of a channel forming peptide derived from the second transmembrane segment of the alpha subunit of the human spinal cord glycine receptor.
Tomich said chloride ions are hydrogen bond acceptors; consequently, it is hypothesized the hydroxyl function contributes strongly to ion throughput across and/or ion selectivity within the channel structures. Residue replacements in the peptide involving the 13th and 17th positions were designed to correlate hydrogen-bonding strength with selectivity and permeation rates. The hydrogen bonding strengths of the amino acid side-chains correlate directly with anion selectivity and inversely with transport rates for the anion.
According to Tomich, these results will help in optimizing these two counteracting channel properties.
"Your body knows how to separate these things all by itself," Tomich said. "Sodium is usually higher outside the cell, potassium is higher inside the cell and chloride, depending on the cell type, can be the same or different.
"The chemical mechanisms directing chloride binding and transport are poorly understood," he said. "The mechanisms determining how sodium, potassium and calcium get across are much better known. We're trying to find out how chloride actually gets across so we will then be able to manipulate both the transport rates and selectivity."
Tomich began working on this many years ago. Over the past 15 years, his lab has developed more than 200 sequences that showed varied ion transport activity in synthetic membranes, as well as cultured epithelial cells and animals. From all of that they can change virtually the way this ion channel assembles. Some of the compounds that he has designed work at very low concentrations but lack some of the chloride specificity that it once had. Their presentation discussed how the researchers back-designed the channel pore so it can be more specified for chloride.
"Our goal is to make a drug that would work efficiently and effectively at low doses," Tomich said. "We have some early designs that are highly selective for chloride, but you'd have to give them a lot of the compound to see the effect."
- Membrane Active, Synthetic Organic Compounds Symposium of the American Chemical Society's national meeting and exposition in Washington, D.C., August 28, 2005
Kansas State University
Tomich's research is funded in part by a grant from the National Institute of General Medical Sciences at the National Institutes of Health.
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