EAPSI: Understanding the Chemistry behind Cystic Fibrosis

Harris Taylor A, Tampa FL

Investigators

Abstract

Cystic Fibrosis (CF) is a genetic disorder characterized by the build-up of a thick sticky mucus at the epithelial surface of organs such as the lungs, pancreas, gut and gastrointestinal tract, giving rise to complications such as chronic infection, inflammation and/or organ failure. CF is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), in which there are over 2000 different mutations. Currently, many of the medicines for CF are symptomatic treatments, used for airway clearance, preventing infection and inflammation, etc. while very few are used to treat the mutated CFTR protein itself. This work will investigate small molecules capable of binding to and stabilizing a region of the mutated protein, in hopes of improving current treatments used to do so. This will be done using both experimental and computational methods. This research will be conducted at Kwansei Gakuin University (KGU) under the advisement of Dr. Tsukasa Okiyoneda, an expert experimentalist in CF research. This collaboration provides access not only to Dr. Okiyoneda's knowledge-base, but also to the resources at KGU in which can be used to validate computational findings. As stated, there are over 2000 mutations of CFTR. Of the 2000, the most common mutation is the ÄF508 (ÄF508-CFTR), which is a deletion of a phenylalanine residue at position 508. This ÄF508 mutation exists in the NBD1 region of the protein. CFTR consists of five domains: membrane spanning domains 1 and 2 (MSD1/2), nuclear binding domains 1 and 2 (NBD1/2), and the regulatory domain (R). This research will focus on finding drugs and/or small molecules that can bind to the NBD1 region of CFTR and stabilize it. Computationally, programs such as Glide, ProBiS and LiSiCA will be used to predict binding sites and binding interactions with several compounds. The data received from the computational efforts will then be applied to experimental techniques by testing the compounds on purified protein from E. coli. This award under the East Asia and Pacific Summer Institutes program supports summer research by a U.S. graduate student and is jointly funded by NSF and the Japan Society for the Promotion of Science.