This dissertation, "Synthetic Ion Channels Based on Peptides and Aminoxy Acid Foldamers: Structure, Activity and Biological Study" by Zongchang, Yang, 楊宗昌, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled SYNTHETIC ION CHANNELS BASED ON PEPTIDES AND AMINOXY ACID FOLDAMERS: STRUCTURE, ACTIVITY AND BIOLOGICAL STUDY submitted by Yang Zongchang for the Degree of Doctor of Philosophy at The University of Hong Kong in May 2014 The exchange of ions and neutral species across cell membranes lies at the center of physiological functions of cells. Nature has developed complex and efficient machineries, termed ion channels, to facilitate and control ion transport. By mimicking functions of natural ion channels, synthetic ion transporters have potentially diverse biological applications, e.g., as antimicrobials, anticancer agents, and potential treatment for channelopathies. However, most synthetic ion transporters ever reported are too large to be drug-like, and knowledge on rational design of effective ion transporters is still limited. In this thesis, a series of synthetic ion channels based on short peptides and small aminoxy acid foldamers, channel structures, structure and activity relationship, and their application as potential treatment for cystic fibrosis are disclosed. Pentapeptides YZC-59 and YZC-78 can self-assemble in their β-sheet conformation into sodium-conducting channels in lipid bilayer membrane. The + - channels formed by molecules of YZC-78 exhibit selectivity for Na over Cl by 3.89 folds. These peptides are the shortest linear peptides that can self-assemble into sodium channels. As short peptides emerge at early stage of the prebiotic Earth, these pentapeptides may plausibly function as primordial ion channels in primitive cellular life. Aminoxy acid foldamers, which have more predictable conformations and better bio-stabilities than natural peptides, have been successfully employed as synthetic ion channel candidates. Structures of three new foldamers YZC-71, YZC-72 and YZC-75 have been characterized by NMR and X-ray crystallography. Six different types of aminoxy acid foldamers have been found to facilitate ion transport across lipid bilayers. The structure and activity relationship (SAR) of ion channels formed by homochiral α-aminoxy acid foldamers have been elucidated by two approaches: analyzing the results of a carefully and systematically designed library; and elaborating the channel structure and transport mechanisms of model compound YZC-125. General rules for improving activity and principles for tuning cation versus anion selectivity have been discovered. In addition, YZC-147 has been found to + + - self-assemble into ion channels with selectivity of K: Na: Cl = 13.15: 3.46: 1. Other new chloride bicarbonate dual-transporters, chloride transporters, chloride sodium dual transporters and sodium transporters are, rather, incidental by-products of this SAR study. In biological study, compound YZC-125, as a model compound, has been found to mediate chloride and bicarbonate transport across Calu-3 apical membrane and facilitate chloride translocation through apical membrane of CFBE41o-. The studies on a focused library of synthetic ion transporters have uncovered the relationship of structures and their effects on I of Calu-3 and CFBE41o- cell lines. This relationship sc is found to be similar to the structure and activity relationship obtained from liposome-based assay, providing a good basis for further drug development. DOI: 10.5353/th_b5312306 Subje