New Projects
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Infectious disease 
Second-generation analogues of the anti-TB drug PA-824. PA-824 is a bioreductive prodrug, and one of the first to act against latent TB; the aim is to retain these activities while increasing potency and solubility and decreasing HERG liability. This project is in collaboration with the Global Alliance for TB Drug Development (New York) and the University of Chicago. [A/Prof Brian Palmer, Prof Bill Denny]
Structure and function of novel streptococcal virulence factors. This HRC-funded project uses structural biology to address the functions of putative virulence proteins identified from the genome of Streptococcus pyogenes. The structures of three such proteins have been solved in the past 18 months.
Inhibition of KDO8P synthase. In this CMB-funded project, PhD student Aidan Harrison, at Massey University, is working to design mechanism-based inhibitors for an enzyme which is involved in the synthesis of lipopolysaccharide, an essential component of bacterial cell walls.
Novel proteins from an animal virus. This collaborative project, involving researchers at Otago and Auckland Universities is primarily FRST-funded, with some support from the CMB. It aims to discover and characterise novel proteins from orf virus, as potential therapeutics.
Mechanisms of antibiotic resistance. This HRC-funded project, led by Prof. Peter Metcalf, is analysing bacterial proteins that have the ability to inactivate commonly used antibiotics. Knowledge of how this occurs will be valuable for the design of newgeneration aminoglycoside antibiotics.
Structure and function of the staphylococcal superantigen-like SSL7. SSL7 is a novel secreted toxin from S. aureus which binds strongly to IgA and complement C5. The organism uses SSL7 to evade complement mediated defences. Natasha Willoughby, a PhD student, is examining the role of SSL7 in inhibition of phagocytosis and is also using mutagenesis to identify the separate binding sites.
The structure and function of the staphylococcal superantigen-like SSL13. PhD student Amanda Taylor is working on SSL13, another of the secreted toxins produced by S. aureus which appears to interfere with blood coagulation by binding to Factor XIII. SSL13 binds strongly to endothelial cells, the cells that line the blood vessels. One theory is that the toxin promotes extravasation - a process where the bacteria migrates through the vessel wall into the surrounding tissue.
The structure and function of the staphylococcal superantigen-like toxin SSL5. SSL5 was the first of the SSL’s to have its structure determined. SSL5 has some interesting properties but its real function remains elusive. It binds almost all cells, and interestingly causes the rapid uptake of small molecules into the cell without killing the cell, suggesting that it is a pore forming toxin. SSL5 is being studied by Dr. Indira Basu, a CMB Research Fellow.
The structure and function of staphylococcal superantigen-like proteins SSL3 and SSL9. SSL9 has been found to inhibit complement mediated cell killing. Determination of the three-dimensional structure of SSL9 is almost complete and will be used to identify specific binding sites by amino acid mutagenesis. SSL3 has been found to bind strongly to CD10 positive cells (pre-B cells and granulocytes). SSL3 is unique in that it has an extra N-terminal domain compared to the other SSLs. This is the topic of Nicola Jackson’s PhD project.
Novel pathogenicity factors from Streptococcus pyogenes. Dr. Proft, a CMB associated scientist, has used bioinformatics to identify novel virulence factors for group A Streptococci – a very common human pathogen. Several novel genes have been identified, and one has been identified as a cell surface sortase which directs proteins to the cell surface of the bacteria. The structure of the sortase is being determined in Prof. Bakers lab.
First enantioselective synthesis of the potent anti-Helicobacter pylori agents, the spirolaxines. These compounds were initially isolated in small quantities from a white rot fungi by Pfizer. The execution of their chemical synthesis, by Professor Margaret Brimble and PhD student James Robinson, allows access to more material for further biological evaluation and work on the synthesis of more potent analogues is ongoing (published in the premiere chemical communications journal J. Chem. Soc. Chem. Commun., 2005, 1560-1562).
Superantigen-decorated virus-like particles as improved vaccines. Dr. John Taylor and PhD student Ms. Julie Hill (School of Biological Sciences) are working to increase the immune response to virus infection by developing vaccines the could overcome the weak immune response in humans during persistent virus infections by coupling to modified bacterial superantigens.
Cancer
Second-generation analogues of the hypoxia prodrug tirapazamine. The major goals here were to improve on the solubility, tissue diffusion rate and hypoxic cell selectivity of tirapazamine; a clinical candidate (PR-205) has just been selected. In collaboration with Stanford University, funded by NIH and Proacta. [Dr Michael Hay, Prof Bill Wilson, Prof Bill Denny]
NitroCBIs as hypoxia-activated prodrugs. We have recently shown a clearly-defined sub-class of nitrobenzindolines to have greater potency and much higher hypoxic selectivity than tirapazamine), and are developing these towards clinical candidate status. Funded by NERF. [Dr Moana Tercel, Prof Bill Wilson, Prof Bill Denny]
Drugs selectively cytotoxic to cells that over-express the transcription factor HIF-1á. The transcription factor HIF-1á is elevated under hypoxia (due to inhibition of degradation), and activates a number of growth stimulatory pathways; we are currently developing hits found in a high-throughput screen. In collaboration with Stanford University, funded by NIH. [Prof Amato Giaccia, Prof Bill Denny]
Inhibitors of the pore-forming protein perforin. Project to develop inhibitors of perforin, secreted by cytotoxic lymphocytes, as a therapy for graft-versus-host disease and transplant rejection. In collaboration with the Peter McCallum Cancer Institute (Melbourne), and funded by PerforX Ltd. [Dr Julie Spicer, Prof Bill Denny]
Inhibitors of DNA methyltransferase. Development of a new class of inhibitors of the DNA-binding methyl transferase enzyme Dmnt1, for use in cancer therapy. A collaboration with Supergen Inc, San Diego, USA. [Prof Bill Denny]
Inhibitors of PI3 kinase isoforms. The PI3K class of lipid kinases influence many cell signalling pathways, and selective inhibitors of the different isoforms have potential roles in cancer, thrombosis and asthma therapy. In collaboration with MMP. [A/Prof Gordon Rewcastle, Prof Peter Shepherd, Prof Bruce Baguley, Prof Bill Denny]
Towards the development of new anti-folate drugs. Folate is an essential vitamin but compounds based on it (anti-folates) can have potent anti-cancer activity. In this HRCfunded project, led by Assoc. Prof. Peter Metcalf and Dr. Paul Young, a key metabolic enzyme folylpolyglutamate synthetase is being investigated with a goal of designing improved anti-folate compounds.
Synthesis of peptide components for use in human cancer vaccines. Peptides are attractive components of vaccines for cancer therapy, since the main signals that stimulate immune cells to attack cancer cells come from peptides. This project uses novel synthetic chemistry to add new complexity to peptide-based vaccines, by decorating peptides with mannose molecules in order to improve their targeting into the immune system. This CMB supported project is being carried out by PhD student Renata Kowalczyk, supervised by Prof. Margaret Brimble and Assoc. Prof. Rod Dunbar.
Diabetes and cardiovascular disease
Structural analysis of an enzyme implicated in diabetic complications. This research, carried out by PhD student Peter Brown with support from the CMB and an Enterprise Scholarship, aims to solve the structure of human myo-inositol oxygenase (MIOX). X-ray data have been collected and the structure is nearing completion.
Understanding How Glucose Regulates Protein Levels in Cells. Diabetes is characterised by increased circulating glucose levels and these are implicated in the development and progression of the debilitating complications that are associated with diabetes. This project will investigate a novel pathway by which glucose can directly modulate the levels of proteins that in turn contribute to the progression of complications. This project is being carried out in Prof. Peter Shepherd’s laboratory is funded by the HRC.
Novel first-in-class hormone-based treatment for insulin resistance.Prof. Garth Cooper’s Proteomics group has discovered a novel neural mechanism that regulates muscle-fat metabolism. Since excess muscle fat is thought to cause insulin resistance, this may offer a potential new route for pharmacotherapy of insulin resistance. The Endocrine/Metabolic Division of the US Food and Drug Administration (FDA) reviewed our experimental data in 2005 (international regulatory validation), with the view to entering human clinical trials for the indication of “insulin resistant type-2 diabetes”, which we expect to begin in 2006.
Two new classes of anti-diabetic drugs that suppress islet â-cell degeneration. Prof. Cooper’s group has discovered two new classes of anti-diabetic agents that act by suppressing islet â-cell degeneration, and expect that these will be developed in global clinical trials as new therapies for the prevention and suppression of type-2 diabetes. Investigation of the molecular mechanisms underlying the biological activities of adiponectin in the liver. Adiponectin is a hormone produced by the adipose tissue that can protect the liver against the complications of diabetes, moderate inflammation and combat the development of cardiovascular disease. CMB PhD student Bronwen Jongbloed is investigating the molecular mechanisms of how adiponectin does this, supervised by Prof. Garth Cooper.
Immune metabolic interactions in liver disease. Fat accumulates in human livers as a result of a variety of factors including diabetes, excessive alcohol consumption and obesity. There are no effective pharmacological treatments available for these diseases. CMB PhD student Catherine Lloyd aims to provide an improved understanding of the molecular and cellular processes underlying the development of fatty liver disease, supervised by Assoc. Prof. Rod Dunbar and Prof. Garth Cooper.
Biotechnology applications for human health
Testing Utility of Superantigen for Improving Antibody Yield in Sheep. Antibodies raised against specific peptides are a vital tool in modern protein biochemistry but the antigenic response to short peptides is often poor, meaning that many peptides do not produce good antibodies. This project, led by Prof. Peter Shepherd, is evaluating whether the use of superantigen will increase the efficiency of antibody production using a range of peptide antigens.
Structure-based design of drugs for treatment of cataracts. This research, carried out by CMB-funded PhD student Blair Stuart at the University of Canterbury, uses structural knowledge of related proteins to design inhibitors for calpain proteins, involved in the formation of cataract.
Protein engineering of an all-purpose binding domain. This project, led by Dr. Vic Arcus, and funded by the CMB and the Marsden Fund, aims to develop OBodies as novel tools for applications in biotechnology. The OBodies are protein domains which can be randomised and selected by phage display to bind a wide diversity of ligands.
Structural analysis of polyhedrin crystals. This research is led by Assoc. Prof. Peter Metcalf and carried out by PhD student Elaine Chiu with support from the CMB and a Bright Futures Scholarship. It aims to analyse naturally-occurring crystals that can encapsulate viruses and protein molecules, and have potential applications for delivery systems in biotechnology.
Structural analysis of the lactoferrin receptor. In this NIH-funded collaborative project with the University of California, Davis, Prof. Ted Baker aims to solve the structure of the intestinal receptor for human lactoferrin, believed to be important for iron uptake by newborn infants.
