14 DAY TRIAL // It may be deadly, but a peptide in the scorpion venom could be the solution against cystic fibrosis and other secretory diseases, as described by a new research published in the "Journal of Biological Chemistry." The new peptide, GaTx1, controls the ions and water flow out of cells via an essential chloride channel.
"Peptide toxins from scorpions, snakes, snails and spiders paralyze prey by blocking nerve or muscle ion channels so the prey can't get away. Those toxins have been enormously useful for studying the potassium, calcium, and sodium channels that they interact with, but this is the first toxin discovered that potently binds to and selectively and reversibly inhibits a chloride channel of known molecular identity," said Nael A. McCarty, an associate professor in the Georgia Institute of Technology's School of Biology.
Chloride channels are important for secretion in many epithelial tissues. The movement of the chloride ion causes an osmotic gradient controlling water flow. In over 70,000 people worldwide experiencing cystic fibrosis, the impairment of water flow in airway cells causes abnormally thick sticky mucus , resulting blockages of the airways and glands.
The issue is caused by a chloride channel, named the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Cystic fibrosis is caused by the mutation of this protein. Mutated CFTR proteins make the chaperone proteins to bind and discard them from the cell. No CFTR proteins means an impairment of the water flow into or out of the cells, causing the cystic fibrosis.
In other conditions, CFTRs are overactive. Such diseases are secretory diarrhea, causing thousands of deaths annually, diarrhea-predominant inflammatory bowel disease, and autosomal dominant polycystic kidney diseases, the fourth main cause of end-stage renal disease in the US.
The team from the Hungarian Academy of Sciences, Emory University and the University of Calgary, employed reversed-phase high-performance liquid chromatography (HPLC) in order to differentiate the new GaTx1 peptide from the venom of the Giant Israeli Scorpion, Leiurus quinquestriatus hebraeus. The new GaTx1 weighed 3.7 kilodaltons and bound to the cytoplasmic side of the CFTR protein. It could explain more on the structure and functioning of the chloride channels; the peptide could also be employed in treating secretory diseases.
"For people with illnesses like secretory diarrhea, GaTx1 could be used to inhibit the channels from opening, in turn decreasing production of the watery diarrhea that often leads to death in patients suffering from cholera and other diarrheal diseases," said McCarty.
"To treat patients with cystic fibrosis, GaTx1 could possibly be used to increase water production, by binding to the chaperone binding sites on the chloride channel. By blocking chaperones from binding, CFTR proteins would not be discarded and thus ions and water would flow from the cells to thin the mucus in the airway. Even though the channels would be misfolded and probably only function at 50% capacity, chloride ions and water would still be transported through the cell. This is better than the alternative of allowing the chaperones to discard all of the CFTR proteins. GaTx1 has the potential to be used as a drug to help patients with cystic fibrosis and these other secretory diseases," he added.