This technology targets two roles of the CFTR protein: one related to the lethal genetic disease, Cystic Fibrosis (CF), and one related to diarrheal diseases that all humans are susceptible to, even if their expression of CFTR is normal.

CFTR forms a chloride ion channel protein in the apical membranes of many epithelial cell types, including the lungs and the intestines. Mutations in the gene encoding CFTR are the cause of CF, the most common lethal autosomal recessive genetic disease among Caucasians. In most CF patients, mutant protein fails to form ion channels that remain open long enough to achieve the amount of flow of chloride in normal CFTR. Hence, drugs that increase the activity of CFTR in those patients, which are referred to as “potentiators,” are of high potential clinical value for CF patients. In specific, drugs that target the extracellular face of CFTR in order to latch it open would be likely to increase CFTR channel activity and thereby recover the amount of chloride secretion seen in subjects that do not have CF.

CFTR also plays an important role in the pathogenesis of secretory diarrhea, which is a leading cause of death across the globe. Pathogens such as Vibrio cholera secrete toxins which cause the irreversible activation of CFTR, allowing the loss of chloride and water that form the watery diarrhea that leads to death if uncontrolled. Secretory diarrhea is a major global health problem, leading to the death of -2 million children under age five each year. The development of molecules that directly disrupt the pathogenesis of secretory diarrhea, until the effects of the toxin are washed out, has not advanced to the point of impacting specific disease targets; the role of CFTR in secretory diarrhea represent a primary target for drug development, since CFTR is expressed in intestinal epithelial cells and is accessible to the extracellular fluid.

Therefore, drugs that target the extracellular face of CFTR, in order to latch it closed would be likely to decrease CFTR channel activity and stop the watery diarrhea that leads to death.

The McCarty lab has established a platform for the identification of peptide sequences that either inhibit CFTR or activate it. This is based upon the use of phage display technology to isolate phage presenting 12-residue peptide sequences that either recognize CFTR when latched closed or latched open, taking advantage of tools that have been developed to control the CFTR state from our prior research. Once phage clones that bear these activities are isolated, they are tested using electrophysiological assays – an approach fundamental to the McCarty lab. When the sequences of these active peptides are determined, we will be able to generate antibody fragments (“nanobodies”) or single-chain antibodies that can be developed as therapeutics.

The successful development of peptide-based drugs to target CFTR, with potential clinical benefit, has not yet been reported. Peptide-based drugs are known to have higher affinity and longer effect than small-molecule drugs. Furthermore, peptide-based drugs can be designed by taking advantage of information gleaned from years of study of the structure of the target protein (CFTR), such as has been underway in the McCarty lab for over 20 years. These studies furthermore have provided background knowledge, not available to the general public, that allows us to control the state in which the CFTR protein exists during the drug discovery and screening phase, thereby enabling the identification of state-specific peptides: peptides that interact with the protein in the open state should serve as activators of CFTR, while peptides that interact with the protein in the closed state should serve as inhibitors of CFTR.