Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/130125
Type: Thesis
Title: Understanding PPARg-Ligand Interactions to Treat Type 2 Diabetes
Author: Frkic, Rebecca Louise
Issue Date: 2021
School/Discipline: School of Biological Sciences : Molecular and Biomedical Science
Abstract: The incidence of type 2 diabetes mellitus (T2DM) is increasing, caused by our growingly obese population among other predisposing factors. In fact, the World Health Organisation has predicted that diabetes will be the 7th leading cause of death by 2030. Despite this, there is a shortage of practical treatments effective at restoring a patient’s sensitivity to insulin. Current treatments of T2DM typically require the combination of multiple therapeutics in highly regulated doses, together with insulin injections. The rising occurrence of T2DM highlights the necessity for an effective treatment to increase insulin sensitivity in T2DM sufferers. The most promising class of antidiabetic compounds are the thiazolidinediones (TZDs), which have an impressive capacity to effectively restore insulin sensitivity. They work by modulating PPARγ, a nuclear receptor central to many roles, including metabolism, inflammation, and the regulation of glucose homeostasis. However, TZDs have been restricted from clinical use due to unfavourable side effects, such as congestive heart failure, loss of bone density, kidney damage, and oedema. The effectiveness of TZDs as insulin sensitisers merits their development to achieve an improved antidiabetic treatment that does not exhibit harmful side effects. It has been established that the side effects associated with TZDs correlate to their transactivation of PPARγ, and their insulin-sensitising properties are attributed to blocking the phosphorylation of Ser273 of PPARγ, a mechanism distinct from classical transactivation. This phenomenon is the basis for current research of T2DM therapies, where the focus is on new and improved compounds which exhibit low transactivation of PPARγ while still blocking phosphorylation of Ser273. This thesis presents a number of peer-reviewed publications which shed light on knowledge gaps in the field of PPARγ research, namely the structural mechanism of an improved partial agonist SR1988, as well as critical developments in understanding the mode of action of non-activating ligands SR10171, SR11023, and SR10221. In addition, the thesis includes publications highlighting the merit of repurposing TZD-like compounds and developing the PPARγ inverse agonist SR1903 for treating inflammation.
Advisor: Bruning, John
Whitelaw, Murray
Richter, Katharina
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 2021
Keywords: Protein structure
PPARgamma
type 2 diabetes
drug discovery
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals
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