Evaluation Of Specificity, Mechanism Of Action And Therapeutic Use Of Peptides That Disrupt T-cell Antigen Receptor
Funder
National Health and Medical Research Council
Funding Amount
$166,885.00
Summary
Molecular disorganisation of receptor assembly renders the receptor incompetent and the cell unable to perform its normal function. In autoimmune diseases where the target is self the ability to stop autoreactive T cells is a therapy. Synthetic compounds known as peptides have been developed in our laboratory with the ability to disrupt cell function and we are at the forefront of such research. We hypothesise that if you prevent the receptor from assembling properly then it will not function. T ....Molecular disorganisation of receptor assembly renders the receptor incompetent and the cell unable to perform its normal function. In autoimmune diseases where the target is self the ability to stop autoreactive T cells is a therapy. Synthetic compounds known as peptides have been developed in our laboratory with the ability to disrupt cell function and we are at the forefront of such research. We hypothesise that if you prevent the receptor from assembling properly then it will not function. The end result is the potential to develop novel drugs with new means to treat inflammation in a number of autoimmune disorders including diabetes, rheumatoid arthritis, multiple sclerosis and psoriasis. Application of this concept is not restricted to immunology or the disruption of the T-cell antigen receptor but has wider therapeutic application to other multicomponent receptors relevant in the field of oncology, endocrinology, and allergy. By design one can produce peptides that will specifically inhibit specific cellular functions based on structure-function relationships. Further research into this area will then allow design of new non-peptide chemical entities based on the original peptide sequence and structure with easier pharmacological handling properties and efficacy. This project aims to define necessary features of the peptide and test it in humans.Read moreRead less
Glutathione Transferase-derived Compounds As Therapeutic Agents
Funder
National Health and Medical Research Council
Funding Amount
$418,516.00
Summary
Inhibition of cardiac calcium ion channels may be an effective new way of improving heart performance in patients with heart failure. This project will investigate how a glutathione transferase enzyme inhibits calcium ion channels in the heart and if small fragments of a muscle specific glutathione transferase can be used to specifically modify cardiac ryanodine receptor function. These fragments will provide the basis for the development of a new therapeutic approach.
Fungal Phospholipases: A Novel Drug Discovery Platform
Funder
National Health and Medical Research Council
Funding Amount
$588,679.00
Summary
Invasive fungal infections are a serious and escalating health issue. They cause severe disease with a high death rate and are very costly to the health system. This is especially the case in immunocompromised patients, such as those with blood malignancies, organ transplant recipients and AIDS. The number of currently available drugs for the treatment of fungal infections is limited and they are, in general, either not very effective or toxic. The development of fungal strains resistant to thes ....Invasive fungal infections are a serious and escalating health issue. They cause severe disease with a high death rate and are very costly to the health system. This is especially the case in immunocompromised patients, such as those with blood malignancies, organ transplant recipients and AIDS. The number of currently available drugs for the treatment of fungal infections is limited and they are, in general, either not very effective or toxic. The development of fungal strains resistant to these drugs is also becoming problematic. There is an urgent need to discover and develop new drugs effective against fungal infections through identifying new targets in the fungal cell and-or targets that prevent the spread of infection in the human host. We were the first to describe an enzyme, phospholipase B (PLB1), which is secreted by the medically important fungus, Cryptococcus neoformans, and is important in invasion of human tissue by the fungus. It is also important in remodelling of membranes in the fungal cell. This enzyme is sufficiently different from human phospholipases to be a good target for antifungal drugs. In this project, we aim to synthesise and test molecules which should inhibit the activity of PLB and in this way block its harmful effects. We will test the effects of such drugs to make sure they do not interfere with human enzyme systems. Inhibitory compounds may also be used to kill the fungal cells, especially if administered together with currently used therapies. The design and development of new antifungal drugs with a novel mode of action represents a major advance in the treatment of fungal disease, and a saving of some A$60000 per affected patient (estimated from a recent US study).Read moreRead less
Long Acting Insulin: Drug Design, In Vitro Activity Through To Animal Model Efficacy
Funder
National Health and Medical Research Council
Funding Amount
$445,011.00
Summary
This research will develop novel insulins that possess improved stability and activity for diabetic patients. The improved pharmacological actions of the modified insulins offer increased treatment options for patients eg. enabling less frequent or invasive medication. Our cross-disciplinary team will (i) design and synthesise insulin derivatives, (ii) explore the activity of the modified insulins by biophysical activity profiles in vitro, (iii) evaluate the in vivo stability and clinical effect ....This research will develop novel insulins that possess improved stability and activity for diabetic patients. The improved pharmacological actions of the modified insulins offer increased treatment options for patients eg. enabling less frequent or invasive medication. Our cross-disciplinary team will (i) design and synthesise insulin derivatives, (ii) explore the activity of the modified insulins by biophysical activity profiles in vitro, (iii) evaluate the in vivo stability and clinical effects.Read moreRead less
Peptidase Inhibitor 16: A New Biomarker For Human Treg
Funder
National Health and Medical Research Council
Funding Amount
$391,262.00
Summary
As autoimmune diseases including type 1 diabetes and IBD are on the increase, there is still great need for novel diagnostic or therapeutic molecules. We have discovered a novel role for a protein called PI16, which we believe is a biomarker for natural regulatory T cells. These cells police the immune system, preventing inappropriate immune responses such as those that cause autoimmune diseases. This project will confirm its suitability for use as a diagnostic or therapeutic biomarker.
Insulin-like Growth Factor Binding Protein-2 Is A Crucial Activator Of Aggressive Behaviour In Cancer Cells
Funder
National Health and Medical Research Council
Funding Amount
$612,885.00
Summary
The insulin-like growth factor (IGF) system, required for normal development and adult life, is often altered in many diseases including cancer. Key regulators of the IGF system are the IGF binding protein (IGFBP) of which IGFBP-2 is the 2nd most abundant. IGFBP-2 may enhance or inhibit the IGFs, but the mechanisms are not clear. This proposal aims to dissect IGFBP-2 action with the ultimate goal to provide knowledge for the development of targeted therapeutic modulators of IGFBP-2 activity.
MMP13 is upregulated in cancer cells and in the tissue that forms around the cancer (stroma). A new MMP13-specific inhibitor reduces breast cancer growth in a mouse model, both at the primary site and also in bone. We will determine the role of MMP13 made by the cancer cells and stroma, respectively, extend the inhibitor work, and identify proteins being cleaved by MMP13. Being a late-stage manifestation, bone metastasis may represent an important clinical trial setting for MMP inhibitors.
The Team brings together a unique grouping of people with backgrounds in molecular biology, medical microbiology, microbiology, marine ecology and immunology to tackle a significant health problem infections caused by bacteria. Using a novel approach, based on understanding how marine organisms specifically interfere with bacterial colonisation, the Team over the past seven years has identified a group of compounds that represent a novel group of antibiotics. Publications and patenting by the Te ....The Team brings together a unique grouping of people with backgrounds in molecular biology, medical microbiology, microbiology, marine ecology and immunology to tackle a significant health problem infections caused by bacteria. Using a novel approach, based on understanding how marine organisms specifically interfere with bacterial colonisation, the Team over the past seven years has identified a group of compounds that represent a novel group of antibiotics. Publications and patenting by the Team has demonstrated that the Team is at the forefront of research in this area. The novel antibiotics work by preventing bacteria sticking to surfaces and by preventing the bacteria from releasing toxins. The studies will concentrate on those bacteria that produce infections in the lungs (acute pneumonia), eyes (corneal infection), ear (middle ear disease), and abscesses.Read moreRead less
Design And Use Of Human Hematopoietic Prostaglandin D2 Synthase Inhibitors In Allergic Asthma And Bone Diseases
Funder
National Health and Medical Research Council
Funding Amount
$517,960.00
Summary
Many currently used non-steroidal anti-inflammatory drugs are burdened by side effects such as gastrointestinal bleeding or increased risk of heart attack. This is because they ablate the production of a class of molecules called prostaglandins. We believe it is possible to fine tune the action of these drugs and reduce the side effect risk. There is evidence to suggest that only some prostaglandins are involved in inflammation, so the risk of side effect can be reduced by blocking the productio ....Many currently used non-steroidal anti-inflammatory drugs are burdened by side effects such as gastrointestinal bleeding or increased risk of heart attack. This is because they ablate the production of a class of molecules called prostaglandins. We believe it is possible to fine tune the action of these drugs and reduce the side effect risk. There is evidence to suggest that only some prostaglandins are involved in inflammation, so the risk of side effect can be reduced by blocking the production of only a small set. One prostaglandin, prostaglandin D2, is known to cause many characteristics of allergic asthma and may also contribute to osteoarthritis, although the evidence for this is contradictory. We will determine any therapeutic benefit to blocking the production of prostaglandin D2 in these diseases by developing compounds that only inhibit the enzyme responsible for its production.Read moreRead less