|Title:||The Development of Isoform-Selective Dynamin Modulators|
|Publisher:||University of Sydney.|
Children's Medical Research Institute.
Children's Hospital at Westmead Clinical School.
|Abstract:||Dynamin I (dynI) is essential for synaptic vesicle endocytosis in neurons, while dynamin II (dynII) is required for diverse cell functions (clathrin-mediated endocytosis, cytokinesis and actin dynamics). The development of isoform-specific dynamin modulators (potential drugs) would provide important tools to enable dissection of the cellular roles for each isoform and to ultimately target human diseases. The first successful large-scale expression and purification of recombinant rat dynII from transiently transfected Sf21 insect cells in a bioreactor was developed together with a unique normalised GTPase assay, that have enabled for the first time systematic screening of chemical compound libraries for isoform-selective dynamin modulators (either inhibitors or stimulators). A large number of dynII inhibitors were revealed, across all chemical classes studied, representing the only dynII inhibitors since dynasore. The first isoform-selective dynamin inhibitors were found within a new Sulfonadyn series. Among the compounds that stimulate dynamin a very high dyn isoform-selectivity was discovered within Ryngo series (>160-fold selectivity for dynII). Overall, this provides new tools to probe the diverse biological functions of dynamin. The work also provides essential groundwork for new branch of pharmacology and enables future drug development studies that may lead to new drugs for diverse human diseases (epilepsy and cancer).|
|Access Level:||Access is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.|
|Rights and Permissions:||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work:||PhD Doctorate|
|Type of Publication:||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
|MARIANA Anna - Final Thesis.pdf||5.55 MB||Adobe PDF|
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