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
Design and Development of HIV-1 Integrase Inhibitors Based on a Natural Product Lead. HIV/AIDS is a significant health problem with over 40 million people infected with HIV worldwide. Resistance to current drugs is rising rapidly and new therapeutics are urgently needed. This project will bring together local expertise in organic synthesis and virology in order to develop new and better treatments for HIV/AIDS. Ultimately, Australians with HIV may benefit directly from anti-HIV compounds produce ....Design and Development of HIV-1 Integrase Inhibitors Based on a Natural Product Lead. HIV/AIDS is a significant health problem with over 40 million people infected with HIV worldwide. Resistance to current drugs is rising rapidly and new therapeutics are urgently needed. This project will bring together local expertise in organic synthesis and virology in order to develop new and better treatments for HIV/AIDS. Ultimately, Australians with HIV may benefit directly from anti-HIV compounds produced and may also benefit from advances in our understanding of this elusive virus resulting from the project.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
Raman and synchrotron spectroscopy of nano-scale drug interactions and molecular processes in single living cells. The need for potent low-cost drugs is ever increasing, yet effective ways to screen for new drugs remain elusive. A spectroscopic approach to screening drugs in living cells would seem a logical alternative to chemically based and morphological methods that are the status quo. In this context we are developing methodology to analyse molecular target sites in single living cells for ....Raman and synchrotron spectroscopy of nano-scale drug interactions and molecular processes in single living cells. The need for potent low-cost drugs is ever increasing, yet effective ways to screen for new drugs remain elusive. A spectroscopic approach to screening drugs in living cells would seem a logical alternative to chemically based and morphological methods that are the status quo. In this context we are developing methodology to analyse molecular target sites in single living cells for two of the most devastating diseases to afflict human kind, namely malaria and cancer. New ways of rapidly screening drugs in living cells prior to clinical trials will save an enormous amount of time, money and ultimately lives.Read moreRead less
Membrane structure and lipid interactions of the pore-forming toxin Equinatoxin II by NMR. The structure of Equinatoxin II, a pore-forming protein, will be determined in model cell membranes using solid-state NMR spectroscopy. The relationship of molecular structure to bioactivity and the nature of the pore-forming mechanism of this toxin will be determined. The results will aid in understanding how toxins lyse cells and could lead to the design of improved antibiotic peptides. Currently the st ....Membrane structure and lipid interactions of the pore-forming toxin Equinatoxin II by NMR. The structure of Equinatoxin II, a pore-forming protein, will be determined in model cell membranes using solid-state NMR spectroscopy. The relationship of molecular structure to bioactivity and the nature of the pore-forming mechanism of this toxin will be determined. The results will aid in understanding how toxins lyse cells and could lead to the design of improved antibiotic peptides. Currently the structure of membrane proteins are difficult to determine and the newly developed techniques used for the structural determination of this membrane-associated protein will be suitable for studying other membrane proteins and receptors of pharmaceutical importance.Read moreRead less
New polymerisation processes for the synthesis of novel biopolymers. Synthetic peptide-based vaccines, formed via polymerisation of small bioactive motifs, possess several advantages over traditional approaches and promise to be the multi-disease targeting vaccines of the future. Disease targets will include influenza and hepatitis C viruses and a toxin from enteropathogenic Escherichia coli. These three diseases are in desperate need of novel vaccine approaches and the chemistries described in ....New polymerisation processes for the synthesis of novel biopolymers. Synthetic peptide-based vaccines, formed via polymerisation of small bioactive motifs, possess several advantages over traditional approaches and promise to be the multi-disease targeting vaccines of the future. Disease targets will include influenza and hepatitis C viruses and a toxin from enteropathogenic Escherichia coli. These three diseases are in desperate need of novel vaccine approaches and the chemistries described in this proposal represent a conceptual leap over traditional, and so far ineffective approaches investigated thus far. Synthetic antifreeze proteins and bioelastomers will also be constructed using our catalysis driven polymerisation process and applied to unmet medical and industrial needs.Read moreRead less
New methods for the synthesis of stable cyclic peptides. This proposal will design, synthesise and evaluate novel carbocyclic analogues of cyclic peptides which have application in the treatment of pain, diabetes management, malaria, and cancer therapy and diagnosis. The carbocyclic analogues will have improved biostability and will also provide the opportunity for oral administration. Carbacyclic analogues of insulin could lead to improved treatment of Australia's 1.2 million diabetics includi ....New methods for the synthesis of stable cyclic peptides. This proposal will design, synthesise and evaluate novel carbocyclic analogues of cyclic peptides which have application in the treatment of pain, diabetes management, malaria, and cancer therapy and diagnosis. The carbocyclic analogues will have improved biostability and will also provide the opportunity for oral administration. Carbacyclic analogues of insulin could lead to improved treatment of Australia's 1.2 million diabetics including many Aboriginal Australians who are particularly susceptible to Type II diabetes and its debilitating complications.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100010
Funder
Australian Research Council
Funding Amount
$720,000.00
Summary
A 5-D Correlative Imaging Platform: Combining the strengths of light and electron microscopy. This will be Australia's first dedicated five-dimensional multiphoton-microscopy platform, allowing observation of dynamic structures across different length and time scales under controlled temperatures, followed by high-resolution electron microscopy studies on the same samples. This platform will provide a unique characterisation tool to Australia's top-flight investigators, and so contribute to the ....A 5-D Correlative Imaging Platform: Combining the strengths of light and electron microscopy. This will be Australia's first dedicated five-dimensional multiphoton-microscopy platform, allowing observation of dynamic structures across different length and time scales under controlled temperatures, followed by high-resolution electron microscopy studies on the same samples. This platform will provide a unique characterisation tool to Australia's top-flight investigators, and so contribute to the nation's research priorities. It will enable: fundamental studies of cancer, neural diseases and immune disorders; the development of frontier technologies, such as smart nanomaterials, biosensors and targeted drug delivery; and applied research to help plants and soils adapt to climate variability, and to increase sustainable use of water.Read moreRead less
The roles of metal ions in glucose metabolism and the treatment of diabetes. Metal supplements, such as chromium and vanadium are consumed widely for their purported fat reduction and anti-diabetic activities. However, much is still to be learnt about the efficacy and safety of such metal ions when they are taken in supplements and whether they have an essential role in the prevention of diabetes or, in some instances, are a risk factor for cancer. The research will provide an understanding of ....The roles of metal ions in glucose metabolism and the treatment of diabetes. Metal supplements, such as chromium and vanadium are consumed widely for their purported fat reduction and anti-diabetic activities. However, much is still to be learnt about the efficacy and safety of such metal ions when they are taken in supplements and whether they have an essential role in the prevention of diabetes or, in some instances, are a risk factor for cancer. The research will provide an understanding of how these metal complexes exert their anti-diabetic effects and how they can be made safer and/or more efficacious for the treatment of type 2 diabetes, which is a rapidly expanding epidemic in developed countries. Read moreRead less
Design and Mechanistic Studies of Metal-Based Anti-Diabetic Drugs. Metal supplements, such as chromium and vanadium, are consumed widely for their purported fat reduction and anti-diabetic activities. However, much is still to be learnt about the efficacy and safety of such metal ions and whether they have an essential role in the prevention of diabetes or, in some instances, are a risk factor for cancer. The research will provide a fundamental understanding of how these metal complexes exert th ....Design and Mechanistic Studies of Metal-Based Anti-Diabetic Drugs. Metal supplements, such as chromium and vanadium, are consumed widely for their purported fat reduction and anti-diabetic activities. However, much is still to be learnt about the efficacy and safety of such metal ions and whether they have an essential role in the prevention of diabetes or, in some instances, are a risk factor for cancer. The research will provide a fundamental understanding of how these metal complexes exert their anti-diabetic effects and how they can be made safer and/or more efficacious for the treatment of type 2 diabetes, which is a rapidly expanding epidemic in developed countries. Read moreRead less