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
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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0775562
Funder
Australian Research Council
Funding Amount
$500,000.00
Summary
The Melbourne Nanofabrication Facility. Australia is desperately short of facilities for actual fabrication, prototyping and construction of advanced micromechanical and nanoscale systems. This is impeding both academic researchers and industrial developers in the materials, optics and biotechnological industries. The proposed instrument would complete the development of Australia's newest high resolution microscopy centre and enable a wide range of users to image, measure, build and design comp ....The Melbourne Nanofabrication Facility. Australia is desperately short of facilities for actual fabrication, prototyping and construction of advanced micromechanical and nanoscale systems. This is impeding both academic researchers and industrial developers in the materials, optics and biotechnological industries. The proposed instrument would complete the development of Australia's newest high resolution microscopy centre and enable a wide range of users to image, measure, build and design complex nanostructures at the atomic level and upwards. Read moreRead less
Drug targets in malaria parasites. Malaria is rampant throughout our Region and hinders the economies of our neighbours reducing regional prosperity and stability. Australian security and aid personnel deployed in the Region contract malaria infections and global warming could bring malaria-carrying mosquitoes south to Sydney. Australia is pre-eminent in malaria research, making lead discoveries in vaccine and drug development. However, we lack crucial resources to study the parasite in the mo ....Drug targets in malaria parasites. Malaria is rampant throughout our Region and hinders the economies of our neighbours reducing regional prosperity and stability. Australian security and aid personnel deployed in the Region contract malaria infections and global warming could bring malaria-carrying mosquitoes south to Sydney. Australia is pre-eminent in malaria research, making lead discoveries in vaccine and drug development. However, we lack crucial resources to study the parasite in the mosquito phase of its life cycle. The Federation Fellowship will create a malaria mosquito facility to redress this crucial gap in our capability. The Fellowship will double as foreign aid investment by enhancing our capacity to protect ourselves as well as supporting our neighbours.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
Intrinsically Unstructured Proteins (IUPs): NMR characterization, prediction, and application to malarial proteome. Determination of protein structures with longer DR by NMR will enrich the DR dataset and provide a deeper understanding of protein structure-function relationships and protein folding pathways. The proposal will also provide valuable information in the key applied area of target selection in structural biology. Not all current web services are freely accessible and available servi ....Intrinsically Unstructured Proteins (IUPs): NMR characterization, prediction, and application to malarial proteome. Determination of protein structures with longer DR by NMR will enrich the DR dataset and provide a deeper understanding of protein structure-function relationships and protein folding pathways. The proposal will also provide valuable information in the key applied area of target selection in structural biology. Not all current web services are freely accessible and available services can be improved further by using more reliable training dataset or more effective algorithms, development of a national DR predictor will help Australian structural biologists increase the success rate of structure determination and provide greater insight into a range of proteomes.Read moreRead less
Special Research Initiatives - Grant ID: SR0354892
Funder
Australian Research Council
Funding Amount
$40,000.00
Summary
The Australian Protease Network. Proteases are pivotal enzymes during birth, life, ageing and death of all organisms. Proteases regulate most physiological processes by controlling protein activation, synthesis and turnover and are essential for replication and spread of viruses, bacteria and parasites that cause infectious diseases. Blockbuster drugs and diagnostics already target a few proteases. Australians have made innovative contributions individually to understanding and regulating these ....The Australian Protease Network. Proteases are pivotal enzymes during birth, life, ageing and death of all organisms. Proteases regulate most physiological processes by controlling protein activation, synthesis and turnover and are essential for replication and spread of viruses, bacteria and parasites that cause infectious diseases. Blockbuster drugs and diagnostics already target a few proteases. Australians have made innovative contributions individually to understanding and regulating these enzymes. However this initiative aims to network their efforts by value-adding to the current protease research through promoting national and international collaborations to improve our understanding of biology, and encourage exploitation of proteases/inhibitors/receptors for pharmaceutical and industrial applications.Read moreRead less
Reducing the fat burden: Identification of novel cellular and molecular targets for alleviating skeletal muscle insulin resistance. Insulin resistance and the associated consequences are a major public health problem in Australia and cost the healthcare system >$1.1 billion/year. Exercise training and thiaziolidinedione (TZD) treatment are therapies that partially ameliorate insulin resistance through distinct and independent mechanisms. However, neither intervention represents a viable long-ter ....Reducing the fat burden: Identification of novel cellular and molecular targets for alleviating skeletal muscle insulin resistance. Insulin resistance and the associated consequences are a major public health problem in Australia and cost the healthcare system >$1.1 billion/year. Exercise training and thiaziolidinedione (TZD) treatment are therapies that partially ameliorate insulin resistance through distinct and independent mechanisms. However, neither intervention represents a viable long-term strategy: exercise training has low compliance, while chronic TZD use is associated with several adverse side effects (edema, weight gain etc.). We will investigate the metabolic, cellular and molecular mechanisms by which these therapies each exert their positive effect on insulin action with the aim of identifying novel targets for future drug interventions. Read moreRead less
Evolution of a protein fold from toxin to physiological regulator: an endogenous potassium channel blocker in humans. A potassium channel blocking peptide employed by sea anemones as a toxic component of their venom is also found in proteins from a number of higher organisms, including man. In most of these proteins the function of this toxin domain is unknown. This project aims to define the structure and function of this domain in a human protein, matrix metalloprotease 23, which has possible ....Evolution of a protein fold from toxin to physiological regulator: an endogenous potassium channel blocker in humans. A potassium channel blocking peptide employed by sea anemones as a toxic component of their venom is also found in proteins from a number of higher organisms, including man. In most of these proteins the function of this toxin domain is unknown. This project aims to define the structure and function of this domain in a human protein, matrix metalloprotease 23, which has possible roles in prostate and other cancers. Our results will not only be of interest in tracing the structural and functional evolution of this toxin domain but will also provide valuable clues to its role in both the normal physiological function of matrix metalloprotease 23, as well as its potential pathological role in cancer.Read moreRead less
Targeted isolation of specific marine bacterial species associated with higher organsims for the purpose of discovering new antimicrobial compounds. Specific bacterial species that are commonly found in association with marine plants and animals often produce active secondary metabolites. The aim of this project is to apply our understanding of these bacterial-host associations to the targeted isolation of novel antimicrobials from the marine environment. While these new compounds will undoubted ....Targeted isolation of specific marine bacterial species associated with higher organsims for the purpose of discovering new antimicrobial compounds. Specific bacterial species that are commonly found in association with marine plants and animals often produce active secondary metabolites. The aim of this project is to apply our understanding of these bacterial-host associations to the targeted isolation of novel antimicrobials from the marine environment. While these new compounds will undoubtedly have a number of commercial applications this project focuses on the development of products for dental hygiene in animals. Generally, the urgent need for new antimicrobial compounds to combat the growing number of microbes that are resistant to current antibiotics highlights the importance of this project.Read moreRead less