dc.contributor.advisor | Hwang, Tzyh-Chang | eng |
dc.contributor.author | Yeh, Han-I | eng |
dc.date.issued | 2019 | eng |
dc.date.submitted | 2019 Summer | eng |
dc.description | Includes vita | eng |
dc.description.abstract | [ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] As the culprit behind cystic fibrosis (CF) is the dysfunction of the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), pharmacological reagents targeting CFTR may hold the key to the ultimate cure of CF. In this thesis, we present the studies in the mechanisms of action for CFTR potentiators, the small molecules that enhance the functions of CFTR. Using the patch-clamp technique, we demonstrated that the permeant anion nitrate modulates CFTR gating through a mechanism similar to the FDA-approved CFTR potentiator VX-770 (ivacaftor). Via separate sites of action, VX-770 and nitrate stabilize the open channel conformation of CFTR in an energetically additive manner. Next, we investigated the action of a novel CFTR potentiator, GLPG1837, and showed that despite their different chemical structures, GLPG1837 and VX-770 share the same mechanisms of action on CFTR gating and compete for a common binding site in the transmembrane domains of CFTR. An allosteric modulation model is further proposed to explain how the affinity and efficacy of both potentiators are determined by the energetic coupling between drug binding and channel gating. Finally, we combined molecular docking and patch-clamp technique to identify the binding site(s) for GLPG1837 and VX-770. | eng |
dc.description.bibref | Includes bibliographical references. | eng |
dc.format.extent | xi, 222 pages : illustrations | eng |
dc.identifier.uri | https://hdl.handle.net/10355/76161 | |
dc.identifier.uri | https://doi.org/10.32469/10355/76161 | eng |
dc.language | English | eng |
dc.publisher | University of Missouri--Columbia | eng |
dc.relation.ispartofcommunity | University of Missouri--Columbia. Graduate School. Theses and Dissertations | eng |
dc.rights | Access is limited to the campuses of the University of Missouri | eng |
dc.subject.other | Pharmacology | eng |
dc.subject.other | Biology | eng |
dc.title | Molecular mechanisms of action for CFTR potentiators | eng |
dc.type | Thesis | eng |
thesis.degree.discipline | Medical pharmacology and physiology (MU) | eng |
thesis.degree.grantor | University of Missouri--Columbia | eng |
thesis.degree.level | Doctoral | eng |
thesis.degree.name | Ph. D. | eng |