Studies Of Metabolites Of Synthetic Flavonols For The Treatment Of Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$207,440.00
Summary
Cardiovascular disease, including heart attack and stroke, is the leading killer of Australians. A promising new drug, NP202, can reduce the amount of tissue damaged from a heart attack; however, its mechanism of action remains obscure. NP202 is metabolized to a range of compounds, one of which is partly responsible for its beneficial effects. In this project we will identify other metabolites of NP202 and characterize their biological activity to gain insight into its mechanism of action.
Development Fo A Novel Treatment For Asthma: The Identification Of Lead Small Molecule Antagonists Of The IL-13/IL-13 Re
Funder
National Health and Medical Research Council
Funding Amount
$99,750.00
Summary
In developed countries Asthma ranks among the most common chronic illnesses. Over two million Australians now have this condition and the cost to our community is estimated to be in excess of $720 million per annum. In 1996 researchers at The Walter and Eliza Hall Institute discovered a new member of the cytokine receptor family, IL-13Ra1, which further research has strongly implicated in the pathology of this disease. The main goal of the proposed research is to discover small molecule antagoni ....In developed countries Asthma ranks among the most common chronic illnesses. Over two million Australians now have this condition and the cost to our community is estimated to be in excess of $720 million per annum. In 1996 researchers at The Walter and Eliza Hall Institute discovered a new member of the cytokine receptor family, IL-13Ra1, which further research has strongly implicated in the pathology of this disease. The main goal of the proposed research is to discover small molecule antagonists of IL-13Ra1 and to identify those suitable for development as novel asthma therapeutics.Read moreRead less
Rapid HIV-1 Tropism Testing Using Novel, Soluble Mimics Of The HIV-1 Coreceptors CCR5 And CXCR4
Funder
National Health and Medical Research Council
Funding Amount
$163,426.00
Summary
This proposal seeks to develop an inexpensive assay to determine whether HIV patients will benefit from treatment with new drugs referred to as CCR5 antagonists. These are effective against HIV strains that use the CCR5 coreceptor, therefore a patient�s HIV coreceptor usage must be assessed before commencing therapy. Current assays are complicated, slow and expensive. Using novel, soluble mimics of the coreceptors we will develop an ELISA based test that can be operated using standard equipment.
Recombinant Bacteria Expressing Oligosaccharide Receptor Mimics For Prevention Of Enteric Infections
Funder
National Health and Medical Research Council
Funding Amount
$451,056.00
Summary
Gastrointestinal infectious diseases kill more than 3 million people each year. The principal microbial pathogens responsible for these infections are known to exploit oligosaccharides on the surface of host cells as receptors for ahesins or toxins. We have developed (and patented) a novel anti-infective strategy, based on mimicry of oligosaccharide receptors for toxins and adhesins produced by enteric pathogens on the surface of harmless carrier bacteria. Oral administration of such recombinant ....Gastrointestinal infectious diseases kill more than 3 million people each year. The principal microbial pathogens responsible for these infections are known to exploit oligosaccharides on the surface of host cells as receptors for ahesins or toxins. We have developed (and patented) a novel anti-infective strategy, based on mimicry of oligosaccharide receptors for toxins and adhesins produced by enteric pathogens on the surface of harmless carrier bacteria. Oral administration of such recombinant probiotics has the potential to prevent enteric infections by binding and neutralizing toxins in the gut lumen and by blocking adherence of the pathogen to intestinal epithelial cells. As a prototypic example, we have developed a bacterium capable of preventing the serious consequences of Shiga toxigenic Escherichia coli (STEC) infections; this agent binds Shiga toxin with very high efficiency and is 100% protective in animal models. The strategy has very broad applications, however, and receptors for virtually any pathogen can be mimicked by expression of appropriate glycosyl transferases in a suitable harmless host bacterium. This proposal involves extension of our existing work to develop therapeutic agents for other important life threatening diarrhoeal diseases including cholera, travellers' diarrhoea, dysentery, antibiotic-associated colitis, rotavirus, etc.Read moreRead less
Inhibitors Of Bacterial Protein Synthesis - A New Class Of Antibiotics
Funder
National Health and Medical Research Council
Funding Amount
$120,000.00
Summary
Pioneering work by CSIRO scientists has identified specific peptide motifs in the DNA replication machinery of bacteria that are critical for the correct functioning of the organism. In collaboration with CI Alewood potent (Kd ~ nM) lead compounds that inhibit bacterial DNA replication have been designed and synthesised. Through the application of a number of novel bioinformatics approaches to the analysis of the complete genome sequences of bacteria, the key sites of interaction of a number of ....Pioneering work by CSIRO scientists has identified specific peptide motifs in the DNA replication machinery of bacteria that are critical for the correct functioning of the organism. In collaboration with CI Alewood potent (Kd ~ nM) lead compounds that inhibit bacterial DNA replication have been designed and synthesised. Through the application of a number of novel bioinformatics approaches to the analysis of the complete genome sequences of bacteria, the key sites of interaction of a number of protein families (DNA synthesis and repair enzymes) with the beta subunit of bacterial DNA Polymerase III have been identified. The nature of the sites, and preliminary experimental data, suggests that the approach will be generally applicable to all species of bacteria. In addition a wide range of novel assays for the identification of inhibitors of the interaction of proteins with the beta subunit have been developed. In this proposal we wish to demonstrate that our in vitro nanomolar inhibitors of the beta subunit can inhibit bacterial cell growth. The development program proposes to develop methods and strategies to gain bacterial cell entry of inhibitors of the interaction of proteins with the beta subunit of bacterial DNA Polymerase III. Proof of concept will be demonstrated by inhibition of bacterial cell growth. Stable compounds with good binding characteristics and able to be taken up by cells will be developed based on structure-function assay results, structural studies and modelling of inhibitors bound to the target. Antimicrobial activity of compounds will be demonstrated in standard FDA approved NCLLS (National Centre of Clinical Laboratory Standards USA) tests. Spectrum of activity will be demonstrated by testing compounds against bacterial species representative of the range of pathogenic organisms in standard FDA assays.Read moreRead less
Evaluation Of Factor Va From The Venom Of The Australian Brown Snake As A Topical And Systemic Anti-bleeding Agent
Funder
National Health and Medical Research Council
Funding Amount
$113,742.00
Summary
Anti-bleeding agents are important pharmaceuticals for use in truama, surgery and several medical conditions to reduce blood loss and the need for blood transfusion. Some Australian snakes contain in their venom a powerful blood clotting agent. This agent mimics the human clotting machinery. In this project, we plan to test purified components of snake venom for an ability to clot human blood. We will undertake laboratory test-tube experiments as well as using an animal model after ethical appro ....Anti-bleeding agents are important pharmaceuticals for use in truama, surgery and several medical conditions to reduce blood loss and the need for blood transfusion. Some Australian snakes contain in their venom a powerful blood clotting agent. This agent mimics the human clotting machinery. In this project, we plan to test purified components of snake venom for an ability to clot human blood. We will undertake laboratory test-tube experiments as well as using an animal model after ethical approval. This project seeks to capture some of the genetic blueprint of an Australian snake, for human benefit by developing a new therapeutic agent based on a venom component. If the experiments are successful, the next stage will be further testing of efficacy and toxicity before seeking approval for clinical trials. The research is supported by the Australian pharmaceutical company QRx Pharma Pty Ltd who will work with Uniquest Pty Ltd to protect intellectual property generated in the project.Read moreRead less
Synthesis And Purification Of Flavivirus-specific Antiviral Factor Mrasal
Funder
National Health and Medical Research Council
Funding Amount
$140,000.00
Summary
In this proposal we suggest to develop an anti-flaviviral compound based on naturally occurring host factors associated with inborn flavivirus resistance observed in mice. We propose to synthesise and purify a mouse protein factor encoded by a gene (Mrasal), which we have previously mapped by mouse genetics and positional cloning to a narrow 300 kb chromosomal region on mouse chromosome 5 carrying flavivirus resistance locus (Flv). When this mouse gene was isolated, sub cloned into a mammalian e ....In this proposal we suggest to develop an anti-flaviviral compound based on naturally occurring host factors associated with inborn flavivirus resistance observed in mice. We propose to synthesise and purify a mouse protein factor encoded by a gene (Mrasal), which we have previously mapped by mouse genetics and positional cloning to a narrow 300 kb chromosomal region on mouse chromosome 5 carrying flavivirus resistance locus (Flv). When this mouse gene was isolated, sub cloned into a mammalian expression vector pcDNA3tag and transiently transfected and expressed in cos-7 and Vero cells, its product conferred antiviral effect to a flavivirus Murray Valley encephalitis (MVE), but not to a non-flavivirus encephalomyocarditis virus (EMCV). Mrasal protein operates as an antiviral host factor and confers a flavivirus specific resistance at the cellular level. It could be directly used for the treatment-cure of acute flavivirus infections in vivo. Our aims are to produce and purify the Mrasal protein for the in vivo delivery as a therapeutic compound into susceptible mice during the acute phase of flavivirus infection: 1. To synthesise and purify Mrasal protein using baculovirus system. 2. To encapsulate the protein into liposomes ready to be used in mice. 3. To perform initial testing in a limited number of susceptible mice.Read moreRead less
Activated Protein C As A Promoter Of Wound Healing
Funder
National Health and Medical Research Council
Funding Amount
$391,650.00
Summary
The healing of wounds is a complex process involving a number of stages, including coagulation, inflammation, remodelling and finally development of full strength skin. Impaired wound healing and-or skin ulcers occur in patients with peripheral arterial occlusive disease, deep vein thrombosis, diabetes, pressure sores and burns. Despite intense investigation, the precise mechanisms associated with impaired healing are poorly understood. APC is a serine protease that plays a central role in physi ....The healing of wounds is a complex process involving a number of stages, including coagulation, inflammation, remodelling and finally development of full strength skin. Impaired wound healing and-or skin ulcers occur in patients with peripheral arterial occlusive disease, deep vein thrombosis, diabetes, pressure sores and burns. Despite intense investigation, the precise mechanisms associated with impaired healing are poorly understood. APC is a serine protease that plays a central role in physiological anticoagulation. APC potently activates gelatinase A, an enzyme that plays a prominent role during the remodelling phase of wound healing and angiogenesis. Our preliminary experiments provide very strong evidence that APC accelerates wound healing using both cultured cells and a rat skin wounding model. There are three aims to this study. The first will use cell culture techniques to investigate the mechanisms of action of APC during wound healing. Secondly, we will expand our pilot studies on the effect of APC as a promoter of wound healing in vivo. These studies will examine the exact dosing and timing regime for APC, using a rat wound healing model. In addition, we will test the effect of APC on slow healing wounds, present in diabetic rats. Thirdly, we will determine whether APC is quantitatively or functionally deficient in human wound fluid derived from slow-healing wounds compared to wounds that heal normally. This is the first time that APC has been implicated in wound healing. It is envisaged that this work will ultimately lead to a novel topical treatment of APC to accelerate slow-healing wounds.Read moreRead less
Development Of Anti-CXCR7 MAbs For The Treatment Of Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$399,998.00
Summary
Fibrosis is a serious biological process that occurs in many disease conditions, including cancer, inflammation and infections. We have produced antibodies to CXCR7, and these antibodies completely inhibit fibrosis in a mouse model. We plan to develop these antibodies in to a suitable drug for human clinical trials.
Targeting Protein Kinase C In Diabetes Management Using Novel Polyunsaturated Fatty Acids
Funder
National Health and Medical Research Council
Funding Amount
$150,000.00
Summary
PKC regulates a diverse range of cellular processes in an isozyme-specific manner. There is strong recent evidence to implicate PKC, especially PKC _, in mediating the actions of glucose in diabetes. This includes the action of glucose in renal glomeruli, retina, aorta and heart of diabetic animals and in cultured cells from these organs. More importantly, inhibition of PKC_ with the PKC_-specific inhibitor, LY333531, blocks the actions of glucose. Recently, our research group designed and synth ....PKC regulates a diverse range of cellular processes in an isozyme-specific manner. There is strong recent evidence to implicate PKC, especially PKC _, in mediating the actions of glucose in diabetes. This includes the action of glucose in renal glomeruli, retina, aorta and heart of diabetic animals and in cultured cells from these organs. More importantly, inhibition of PKC_ with the PKC_-specific inhibitor, LY333531, blocks the actions of glucose. Recently, our research group designed and synthesised a family of novel polyunsaturated fatty acids. One of these, MP5 (_-oxa- 21:3n-3), inhibited high glucose-induced activation of PKC? in cultured mesangial cells as well as in glomeruli of diabetic rats in a relatively selective manner. The overall aim of this proposal is to evaluate the potential for a chemically engineered novel polyunsaturated fatty acid, MP5 (_-oxa-21:3n-3), to treat pathogenesis associated with diabetes by targeting the PKC system. The specific aims are to: 1. Characterise the effects of MP5 on glucose- or advanced glycosylation end product-stimulated activation of protein kinase C (PKC). 2. Determine whether esterification of MP5 into diacylglycerol is essential for the action of MP5 3. Investigate whether MP5 is efficacious at preventing the actions of glucose in vitro e.g. glucose stimulated TGF_ production in mesangial cells, and in vivo in streptozotocin-diabetic rRead moreRead less