Novel target of amiloride analogues - picornaviral RNA polymerase. Picornaviruses cause a range of diseases such as poliomyelitis, meningitis, myocarditis, hepatitis A, neonatal sepsis and common cold. No antiviral treatment is available for these infections. Nearly 50% of antiviral drugs used in medicine are viral polymerase inhibitors; however picornaviral RNA polymerase has been largely overlooked as a drug target. We have discovered a group of compounds that inhibit picornaviral RNA polymera ....Novel target of amiloride analogues - picornaviral RNA polymerase. Picornaviruses cause a range of diseases such as poliomyelitis, meningitis, myocarditis, hepatitis A, neonatal sepsis and common cold. No antiviral treatment is available for these infections. Nearly 50% of antiviral drugs used in medicine are viral polymerase inhibitors; however picornaviral RNA polymerase has been largely overlooked as a drug target. We have discovered a group of compounds that inhibit picornaviral RNA polymerase. This project aims to define the inhibition mechanism and to evaluate a potential use of these compounds for antiviral drug development.Read moreRead less
Improvement of anthracycline chemotherapy by enhancement of apoptotic responses and tumour targeted activation. Improved outcomes for anthracycline anticancer chemotherapy is of clear benefit to the nation. Tumour-localised treatment is expected to lead to improved responses, reduced side-effects and improved quality of life while rational selection of drug combinations is expected to enable treatment of tumours that were previously resistant to anthracyclines. With an aging population in Austra ....Improvement of anthracycline chemotherapy by enhancement of apoptotic responses and tumour targeted activation. Improved outcomes for anthracycline anticancer chemotherapy is of clear benefit to the nation. Tumour-localised treatment is expected to lead to improved responses, reduced side-effects and improved quality of life while rational selection of drug combinations is expected to enable treatment of tumours that were previously resistant to anthracyclines. With an aging population in Australia the incidence of cancer is predicted to rise dramatically - improved treatment outcomes and better use of chemotherapeutics will be of obvious national benefit. The development of new tumour-targeted agents is the subject of joint Intellectual Property between Australia and the USA, offering potential economic benefit. Read moreRead less
Tumour localisation and enhancement of anthracycline anticancer activity. The anthracyclines are one of the most widely used anticancer agents today. If the cytotoxicity of these agents can be localised to tumour cells, or their activity improved, then this will result in improved response rates, less side-effects and an improved quality of life for many patients for whom anthracycline treatment is an important part of their therapy. This will result in enormous national/community benefit to an ....Tumour localisation and enhancement of anthracycline anticancer activity. The anthracyclines are one of the most widely used anticancer agents today. If the cytotoxicity of these agents can be localised to tumour cells, or their activity improved, then this will result in improved response rates, less side-effects and an improved quality of life for many patients for whom anthracycline treatment is an important part of their therapy. This will result in enormous national/community benefit to an aging Australian population that is becoming increasingly more prone to cancer. Read moreRead less
Anticancer drug development: Enhancing the anticancer activity of mitoxantrone. Many cancer sufferers may benefit from this work if we are able to develop more active derivatives of mitoxantrone, or develop procedures to inhibit the repair of DNA lesions induced by mitoxantrone. This may result in therapies with improved response, reduced drug dosage and/or reduced side-effects. Because this work may result in one or more patents, and possibly commercialisation with Australian (and overseas) pha ....Anticancer drug development: Enhancing the anticancer activity of mitoxantrone. Many cancer sufferers may benefit from this work if we are able to develop more active derivatives of mitoxantrone, or develop procedures to inhibit the repair of DNA lesions induced by mitoxantrone. This may result in therapies with improved response, reduced drug dosage and/or reduced side-effects. Because this work may result in one or more patents, and possibly commercialisation with Australian (and overseas) pharmaceutical companies, there are potential commercial benefits to Australia. The "discovery" aspect of this work may also identify other cellular responses to mitoxantrone (ie specific genes which are re-expressed) and this may also reveal new targets to further enhance the activity of this drug.Read moreRead less
Molecular basis for the synergistic potentiation of anthracycline anticancer agents by formaldehyde-releasing prodrugs. AIMS: The overall aim is to develop a full understanding of the molecular basis for the synergistic activation of Adriamycin (and other anthracycline anticancer agents) by formaldehyde-releasing prodrugs such as AN-9.
SIGNIFICANCE: Because Adriamycin is currently one of the most widely used anticancer agents, and this activity has the potential to be dramatically enhanced by t ....Molecular basis for the synergistic potentiation of anthracycline anticancer agents by formaldehyde-releasing prodrugs. AIMS: The overall aim is to develop a full understanding of the molecular basis for the synergistic activation of Adriamycin (and other anthracycline anticancer agents) by formaldehyde-releasing prodrugs such as AN-9.
SIGNIFICANCE: Because Adriamycin is currently one of the most widely used anticancer agents, and this activity has the potential to be dramatically enhanced by the concurrent use of formaldehyde-releasing prodrugs, a biochemical understanding of these processes will provide the basis to exploit this synergy to provide improved treatment outcomes (eg, lower drug doses,reduced side-effects, improved activity against drug-resistanct tumours etc).
EXPECTED OUTCOMES: The long-term outcome of this project is commercialisation to develop products for clinical use based on this synergy (eg, drug/prodrug combinations) and ultimately the development of tumour-directed therapy to yield a tumour-localised anticancer response.Read moreRead less
The “New” Biochemistry of Polyamines: When Metabolic Pathways Collide. Basic biochemistry and the metabolic regulation of proliferation remain as the fundamental building blocks of knowledge in cell biology that have enabled breakthrough advances in biology and medicine. Polyamines are unique and ubiquitous low-Mr amines that play vital roles in many biological processes, including proliferation, DNA/RNA synthesis, etc. This proposal will mechanistically dissect the "new" biochemistry of polyami ....The “New” Biochemistry of Polyamines: When Metabolic Pathways Collide. Basic biochemistry and the metabolic regulation of proliferation remain as the fundamental building blocks of knowledge in cell biology that have enabled breakthrough advances in biology and medicine. Polyamines are unique and ubiquitous low-Mr amines that play vital roles in many biological processes, including proliferation, DNA/RNA synthesis, etc. This proposal will mechanistically dissect the "new" biochemistry of polyamines, as we have discovered that polyamines are regulated by iron at 2-major levels, involving >10-key polyamine pathway proteins. This proposal represents first-in-field studies specifically designed to dissect mechanisms involved in this relationship. Our Central Hypothesis is that iron regulates polyamine metabolism.Read moreRead less
Understanding how RNA editing regulates RNA fate. This project aims to address how RNA editing mediated by ADAR1 alters the interactions of targeted RNA with the innate immune sensing system. ADAR1 editing converts adenosine to inosine within double stranded RNA. It is known that this is key to prevent activation of the innate immune sensor MDA5 by endogenous RNA. However, we do not understand why edited RNA is tolerated and unedited RNA is not. This project will generate new knowledge regarding ....Understanding how RNA editing regulates RNA fate. This project aims to address how RNA editing mediated by ADAR1 alters the interactions of targeted RNA with the innate immune sensing system. ADAR1 editing converts adenosine to inosine within double stranded RNA. It is known that this is key to prevent activation of the innate immune sensor MDA5 by endogenous RNA. However, we do not understand why edited RNA is tolerated and unedited RNA is not. This project will generate new knowledge regarding the effect of editing on how endogenous RNA is perceived by the innate immune system.Read moreRead less
New analgesics based on µ-conotoxins: structure-based design of helical mimetics. Diseases in which voltage-gated sodium channels are implicated are contributors to morbidity and mortality in the Australian population, and this project promises to provide new leads for the future development of drugs to treat such diseases, in particular analgesics for the treatment of chronic pain. The generation of these leads will entail the development of new approaches to mimicking key regions of peptides a ....New analgesics based on µ-conotoxins: structure-based design of helical mimetics. Diseases in which voltage-gated sodium channels are implicated are contributors to morbidity and mortality in the Australian population, and this project promises to provide new leads for the future development of drugs to treat such diseases, in particular analgesics for the treatment of chronic pain. The generation of these leads will entail the development of new approaches to mimicking key regions of peptides and proteins in drug-like molecules. This is a highly interdisciplinary project, spanning structural biology, molecular design, medicinal chemistry, molecular biology and electrophysiology, and the training of PhD graduates with such broad experience represents another national benefit of the project.Read moreRead less
Role of the GxxxG domain in the function of mammalian prion proteins. Prion proteins have been associated with a number of diseases of humans and animals (such as Creutzfeldt-Jakob Disease in humans and BSE, or 'mad-cow' disease in cattle) which have had major public health, social and economic consequences in countries where they have been detected. This project will identify mechanisms by which a highly conserved region of the prion protein plays a role in the conversion to the disease associa ....Role of the GxxxG domain in the function of mammalian prion proteins. Prion proteins have been associated with a number of diseases of humans and animals (such as Creutzfeldt-Jakob Disease in humans and BSE, or 'mad-cow' disease in cattle) which have had major public health, social and economic consequences in countries where they have been detected. This project will identify mechanisms by which a highly conserved region of the prion protein plays a role in the conversion to the disease associated form. This will provide avenues for identifying the normal function of the prion protein, and increase our knowledge of prion biology. This will benefit both in terms of healthy ageing and in protecting the agriculture sector from prion diseases in farmed animals.Read moreRead less
The ApoE Interactome in Human Plasma. In this, the post-genome era, the emphasis has switched from the delineation of genome structure to the tremendous task of characterizing the gene products. One of the important aspects evolving in this new era is the design of strategies that enable identification of global protein-protein interactions, defined by the Human Proteome Organisation as the interactome. This, the apoE interactome in human plasma project, will identify novel interactions between ....The ApoE Interactome in Human Plasma. In this, the post-genome era, the emphasis has switched from the delineation of genome structure to the tremendous task of characterizing the gene products. One of the important aspects evolving in this new era is the design of strategies that enable identification of global protein-protein interactions, defined by the Human Proteome Organisation as the interactome. This, the apoE interactome in human plasma project, will identify novel interactions between plasma proteins and apoE, which is a lipid-binding protein genetically linked to age-related diseases affecting more than 500,000 Australians. This project will therefore provide scope for novel treatments and early detection of disease, namely cardiovascular and Alzheimer's disease.Read moreRead less