|Nicholas P. Gill
B.A., Biochemistry & Molecular Biology
Hendrix College. The best school. Believe me. 2014
Joined the Madden lab in 2015
Engineering peptidomimetic therapuetic leads to enhance ΔF508-CFTR stability at the apical membrane.. Cystic fibrosis (CF) is a lethal autosomal recessive disease in which the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) is mutated. The most common mutation in CFTR, ΔF508, results in three primary intracellular defects: inefficient CFTR folding in the ER and subsequent proteosomal degradation, diminished chloride conductance across the apical membrane, and increased lysosomal degradation upon endocytosis. There is an FDA approved combination therapy that alleviates the aforementioned defects: VX-809 assists proper CFTR folding in the ER and VX-770 enhances the ability of CFTR to efflux chloride at the apical membrane. Combinatorial treatment with VX-809 and VX-770, however, demonstrates modest effects (DFEV1 = 3%) in homozygous ΔF508 CF patients and no efficacy in heterozygous patients. Currently, no therapeutics are designed to stabilize ΔF508-CFTR. Previous research demonstrated that rapid lysosomal degradation of mature CFTR is facilitated by the CFTR associated ligand (CAL), a negative regulator that binds the CFTR C-terminus via a PDZ domain-mediated interaction. To directly address CFTR instability, I am interested in engineering peptidomimetic therapeutic leads to stabilize ΔF508-CFTR at the apical membrane and enhance its ability to conduct chloride. We previously engineered a series of peptide inhibitors of CAL (iCAL) that bind the CAL PDZ domain (CALP) with unprecedented selectivity but with a low target affinity. I am using high-throughput in silico modeling to identify unique chemical moieties that, when coupled to our pre-existing iCAL peptides, enhance the affinity between our therapeutic leads and CALP. By engineering a selective, highly potent iCAL peptidomimetic, we hope to attenuate mutant CFTR defects and, in conjuction with current treatments, augment treatment efficacy in a broader spectrum of CF patients.