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postgraduate thesis: Design, synthesis and characterization of synthetic ion transporters

TitleDesign, synthesis and characterization of synthetic ion transporters
Authors
Issue Date2012
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Zha, H. [查慧艳]. (2012). Design, synthesis and characterization of synthetic ion transporters. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4961743
AbstractIn recent decades, small molecules have been widely applied to the generation of functional ion transporters. Major discoveries disclosed in this thesis include a self-assembled chloride-dependent potassium channel candidate, a physiological chloride and bicarbonate dual-transporter, and a series of efficient synthetic ion transporters. In nature, K+ channels play an important role in Ca2+ signaling, volume regulation, secretion, proliferation, and migration. The extracellular K+ concentration (4 mM) is about 40 times lower than the intracellular K+ concentration (160 mM). The opening of K+ channels consequently generates an efflux of positive charge, which hyperpolarizes or repolarizes the cellular membrane. In this research, by using fluorescence assays, NMR and patch clamp experiments, compound ZHY-CM23 was found to self-assemble into a chloride-dependent K+ selective channel mediating K+ transport across lipid bilayers and cell membranes. In addition, the synthetic K+ channel formed by ZHY-CM23 was found to be capable of generating and modulating the membrane potential of liposomes and to significantly hyperpolarize the resting membrane potential of HEK 293 cells. This finding provides new insight into developing drugs for the treatment of severe human diseases caused by K+ channel malfunction, such as arrhythmia, neurological disorders and autoimmune diseases. Cystic fibrosis is a chronic recessive disease resulting from the loss of function mutations in the gene encoding of the cystic fibrosis transmembrane conductance regulator (CFTR), a member of the ABC family of membrane transporters. Recent findings reveal that restoring bicarbonate transport might be useful for the treatments of the underlying defect in cystic fibrosis. On the basis of fluorescence assays, NMR and short circuit current experiments, the small molecule ZHY-CM11 has been discovered to not only act as a bicarbonate transporter in lipid membranes, but also to induce chloride-dependent bicarbonate secretion in cultured calu-3 epithelia. It is a promising lead compound to be developed for the treatment of cystic fibrosis and other diseases related to chloride and bicarbonate transport defects. Through structural modifications on the bioactive ion channels and the transporters ZHY-CM23 and ZHY-CM11, some valuable information on the structure-activity relationship has been obtained, and a series of potentially biologically applicable synthetic ion transporters have been discovered.
DegreeDoctor of Philosophy
SubjectIon channels
Dept/ProgramChemistry
Persistent Identifierhttp://hdl.handle.net/10722/206532

 

DC FieldValueLanguage
dc.contributor.authorZha, Huiyan-
dc.contributor.author查慧艳-
dc.date.accessioned2014-11-14T23:14:57Z-
dc.date.available2014-11-14T23:14:57Z-
dc.date.issued2012-
dc.identifier.citationZha, H. [查慧艳]. (2012). Design, synthesis and characterization of synthetic ion transporters. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4961743-
dc.identifier.urihttp://hdl.handle.net/10722/206532-
dc.description.abstractIn recent decades, small molecules have been widely applied to the generation of functional ion transporters. Major discoveries disclosed in this thesis include a self-assembled chloride-dependent potassium channel candidate, a physiological chloride and bicarbonate dual-transporter, and a series of efficient synthetic ion transporters. In nature, K+ channels play an important role in Ca2+ signaling, volume regulation, secretion, proliferation, and migration. The extracellular K+ concentration (4 mM) is about 40 times lower than the intracellular K+ concentration (160 mM). The opening of K+ channels consequently generates an efflux of positive charge, which hyperpolarizes or repolarizes the cellular membrane. In this research, by using fluorescence assays, NMR and patch clamp experiments, compound ZHY-CM23 was found to self-assemble into a chloride-dependent K+ selective channel mediating K+ transport across lipid bilayers and cell membranes. In addition, the synthetic K+ channel formed by ZHY-CM23 was found to be capable of generating and modulating the membrane potential of liposomes and to significantly hyperpolarize the resting membrane potential of HEK 293 cells. This finding provides new insight into developing drugs for the treatment of severe human diseases caused by K+ channel malfunction, such as arrhythmia, neurological disorders and autoimmune diseases. Cystic fibrosis is a chronic recessive disease resulting from the loss of function mutations in the gene encoding of the cystic fibrosis transmembrane conductance regulator (CFTR), a member of the ABC family of membrane transporters. Recent findings reveal that restoring bicarbonate transport might be useful for the treatments of the underlying defect in cystic fibrosis. On the basis of fluorescence assays, NMR and short circuit current experiments, the small molecule ZHY-CM11 has been discovered to not only act as a bicarbonate transporter in lipid membranes, but also to induce chloride-dependent bicarbonate secretion in cultured calu-3 epithelia. It is a promising lead compound to be developed for the treatment of cystic fibrosis and other diseases related to chloride and bicarbonate transport defects. Through structural modifications on the bioactive ion channels and the transporters ZHY-CM23 and ZHY-CM11, some valuable information on the structure-activity relationship has been obtained, and a series of potentially biologically applicable synthetic ion transporters have been discovered.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.subject.lcshIon channels-
dc.titleDesign, synthesis and characterization of synthetic ion transporters-
dc.typePG_Thesis-
dc.identifier.hkulb4961743-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineChemistry-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b4961743-
dc.date.hkucongregation2012-

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