K-State Researchers Designing Better Drug To Treat Cystic Fibrosis

A chronic and progressive disease, cystic fibrosis is usuallydiagnosed in childhood. It causes mucus to become thick, dry andsticky. The mucus builds up and clogs passages in the lungs, pancreasand other organs in the body.

There is no cure for cystic fibrosis. Management of the diseasevaries from person to person and generally focuses on treatingrespiratory and digestive problems to prevent infection and othercomplications. Treatment usually involves a combination of medicationsand home treatment methods, such as respiratory and nutritionaltherapies.

Tomich, along with colleagues Takeo Iwamoto, a K-State researchassistant professor, and Shawnalea J. Frazier, senior in biochemistry,Haysville, have been working to understand how ions travel across cellmembranes, specifically the anion part of sodium chloride.

Tomich presented a paper on the trios' findings, "Assessing TheContributions of H-Bonding Donors to Permeation Rates and Selectivityin Self-Assembling Peptides that Form Chloride Selective Pores," Aug.28 at the Membrane Active, Synthetic Organic Compounds Symposium of theAmerican Chemical Society's national meeting and exposition inWashington, 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 thissymposium," Tomich said. "This is a section organized by organicchemists."

Tomich and his collaborators have used a series of single anddouble amino acid substitutions to modulate the activity of a channelforming peptide derived from the second transmembrane segment of thealpha subunit of the human spinal cord glycine receptor.

Tomich said chloride ions are hydrogen bond acceptors;consequently, it is hypothesized the hydroxyl function contributesstrongly to ion throughput across and/or ion selectivity within thechannel structures. Residue replacements in the peptide involving the13th and 17th positions were designed to correlate hydrogen-bondingstrength with selectivity and permeation rates. The hydrogen bondingstrengths of the amino acid side-chains correlate directly with anionselectivity 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 ishigher inside the cell and chloride, depending on the cell type, can bethe same or different.

"The chemical mechanisms directing chloride binding andtransport are poorly understood," he said. "The mechanisms determininghow sodium, potassium and calcium get across are much better known.We're trying to find out how chloride actually gets across so we willthen be able to manipulate both the transport rates and selectivity."

Tomich began working on this many years ago. Over the past 15years, his lab has developed more than 200 sequences that showed variedion transport activity in synthetic membranes, as well as culturedepithelial cells and animals. From all of that they can changevirtually the way this ion channel assembles. Some of the compoundsthat he has designed work at very low concentrations but lack some ofthe chloride specificity that it once had. Their presentation discussedhow the researchers back-designed the channel pore so it can be morespecified for chloride.

"Our goal is to make a drug that would work efficiently andeffectively at low doses," Tomich said. "We have some early designsthat are highly selective for chloride, but you'd have to give them alot of the compound to see the effect."

Tomich's research is funded in part by a grant from the NationalInstitute of General Medical Sciences at the National Institutes ofHealth.