Scorpion peptide based drug for cystic fibrosis and secretory diseases
Researchers have discovered a peptide in scorpion venom that may hold the key to understanding and controlling cystic fibrosis and other secretory diseases.
An international team of researchers describes how a peptide in scorpion venom, called GaTx1, can control the movement of ions and water out of cells by interacting with a crucial 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,” explained Nael A. McCarty, an associate professor in the Georgia Institute of Technology’s School of Biology.
“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.”
Chloride channels are crucial for secretion in many epithelial tissues and they open to allow millions of chloride ions to travel through them and out of epithelial cells. This movement creates an osmotic gradient that allows water to flow.
For cystic fibrosis patients, a lack of water flow in airway cells results in abnormally thick, sticky mucus that commonly causes blockages that obstruct airways and glands. The lack of water flow stems from a problem in a chloride channel called the cystic fibrosis transmembrane conductance regulator (CFTR) protein.
In individuals with cystic fibrosis, the CFTR protein is mutated, often with one or more amino acids deleted, and consequently misfolded. In the most common CFTR mutation leading to cystic fibrosis, the location of the deletion causes the chaperone proteins – which are responsible for quality assurance within cells – to bind to the misfolded proteins and discard them from the cell. Loss of CFTR proteins stops water from flowing into or out of the cells, thereby altering the conditions in the airway, leading to cystic fibrosis.
In other diseases, CFTR channels are overactive, which also causes problems. These include secretory diarrhea, a worldwide health concern causing thousands of deaths per year; diarrhea-predominant inflammatory bowel disease; and autosomal dominant polycystic kidney diseases, the fourth leading cause of end-stage renal disease in the United States.
With collaborators at the Hungarian Academy of Sciences, Emory University and the University of Calgary, the researchers used reversed-phase high-performance liquid chromatography (HPLC) to extract the novel GaTx1 peptide from the complex venom of the Giant Israeli Scorpion, Leiurus quinquestriatus hebraeus.
“We chose this technique because each different peptide has slightly different water solubility and hydrophobicity properties, allowing them to be separated,” explained Julia Kubanek, an associate professor with joint appointments in the Georgia Tech School of Biology and School of Chemistry and Biochemistry.
The researchers collected individual peptides separated by the HPLC system and then applied each to chloride channels to see which peptide was responsible for the overall effects of the venom. They discovered a novel peptide that bound to the cytoplasmic side of the CFTR protein and weighed 3.7 kilodaltons – they called it GaTx1.
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, according to McCarty.
“GaTx1 has the potential to be used as a drug to help patients with cystic fibrosis and these other secretory diseases,” added McCarty.