Activating the body’s hypoxia response as a strategy to treat stroke

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Copyright: Hermanto, Precilia Sonata
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Abstract
Stroke is a major contributor of death and disability in Australia. However, with the lack of treatment options currently available, its impact continues to grow. This places an increasing burden on society, prompting the need to develop alternative pharmacological treatments for the disease. One promising strategy to treat stroke is through activation of the body’s adaptive responses to hypoxia. The body responds to low oxygen (hypoxia) through a transcription factor, HIF-1 (hypoxia inducible factor-1). In low oxygen environments, HIF-1 upregulates hypoxia adaptive genes such as VEGF and erythropoietin that are known to exhibit neuroprotective effects. In the presence of oxygen however, the enzyme PHD2 hydroxylates HIF-1 at a key proline residue, tagging them for degradation. It has been shown that small molecule PHD2 inhibitors e.g. desferrioxamine and N-oxalyl glycine improve recovery in stroke models by acting through the HIF-1 pathway to activate the body’s hypoxia responses. However, they suffer from drawbacks including lack of selectivity. This project investigated the design and synthesis of HIF-1 peptidomimetics as selective inhibitors of PHD2. These peptide mimics contain a prolyl analogue at the hydroxylated proline that is hypothesised to block the hydroxylation site and/or adopt the high affinity (endo) binding conformation to the enzyme. Three proline analogues were proposed for these investigations. Two were successfully synthesised in solution and subsequently incorporated into a 19 amino acid segment of the HIF-1 peptide via SPPS. Docking studies were then performed on the three proposed peptidomimetics to investigate binding to PHD2. All three peptidomimetics were predicted to bind with the prolyl analogue in the high affinity endo conformation. Encouragingly, all three peptides were observed to interact favourably with the active site, proving their feasibility as PHD2 inhibitors. These results provide useful insight into the binding affinity of these peptidomimetics for PHD2. Whether these results are reflected in their PHD2 inhibitory activity is still under investigation. Overall, this work opens promising future directions in the use of peptide-based inhibitors of PHD2 as activators of the body’s hypoxia response
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Author(s)
Hermanto, Precilia Sonata
Supervisor(s)
Hunter, Luke
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Publication Year
2019
Resource Type
Thesis
Degree Type
Masters Thesis
UNSW Faculty
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