Fluorine-labelled proteins for NMR spectroscopy. The technique developed in this project has direct impact on pharmaceutical research: NMR spectroscopy is used routinely to identify chemical compounds that bind to protein targets. This project includes the development of novel assignment techniques of 19F-labelled proteins, so that 19F-NMR can be used to detect specific binding interactions. One of the methods proposed here is designed to reveal structural information about the binding mode in s ....Fluorine-labelled proteins for NMR spectroscopy. The technique developed in this project has direct impact on pharmaceutical research: NMR spectroscopy is used routinely to identify chemical compounds that bind to protein targets. This project includes the development of novel assignment techniques of 19F-labelled proteins, so that 19F-NMR can be used to detect specific binding interactions. One of the methods proposed here is designed to reveal structural information about the binding mode in solution with atomic detail. This knowledge can significantly accelerate drug development. It is otherwise only available from crystal structures that can not always be determined.Read moreRead less
The design and synthesis of angiotensin converting enzyme-2 (ACE2) inhibitors. A vast number of current drugs on the market are inhibitors of enzymes whose action needs to be controlled in order to treat many conditions. This proposal will apply our new approaches to the design of enzyme inhibitors with superior therapeutic action. The benefits of this research reside in new treatments for a range of cardiovascular diseases (the 3rd largest cause of mortality in Australia) and provide a platform ....The design and synthesis of angiotensin converting enzyme-2 (ACE2) inhibitors. A vast number of current drugs on the market are inhibitors of enzymes whose action needs to be controlled in order to treat many conditions. This proposal will apply our new approaches to the design of enzyme inhibitors with superior therapeutic action. The benefits of this research reside in new treatments for a range of cardiovascular diseases (the 3rd largest cause of mortality in Australia) and provide a platform for new biotech companies to be formed in Australia.Read moreRead less
Differential Expression Proteomics: Identification and Quantitation of Peptides and Proteins by Fixed Charge Derivatization and Tandem Mass Spectrometry. The aim of this proposal is to develop novel strategies for the rapid, sensitive and selective identification and quantitation of proteins present in complex mixtures. Specifically, isotopically labeled fixed charge derivatives of peptides containing selected amino acids will be developed that direct the formation of product ions following tan ....Differential Expression Proteomics: Identification and Quantitation of Peptides and Proteins by Fixed Charge Derivatization and Tandem Mass Spectrometry. The aim of this proposal is to develop novel strategies for the rapid, sensitive and selective identification and quantitation of proteins present in complex mixtures. Specifically, isotopically labeled fixed charge derivatives of peptides containing selected amino acids will be developed that direct the formation of product ions following tandem mass spectrometry toward a single fragmentation channel. This approach will provide enhanced selectivity and sensitivity of up to 2 orders of magnitude over existing approaches, and will allow examination, at the protein level, of the complex cellular changes that occur following transformation of cells from a normal to a diseased state.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0775529
Funder
Australian Research Council
Funding Amount
$300,000.00
Summary
Structural elucidation by chemical degradation mass spectrometry using a linear ion trap with electron transfer dissociation. The mass spectrometric instrumentation that we plan to acquire represents a true breakthrough in technology, and will be the first of its kind in operation in Australia. The instrument to be purchased will improve the ability of a wide cross section of researchers to characterize compounds important in fields as varied as medical research, agricultural biotechnology, and ....Structural elucidation by chemical degradation mass spectrometry using a linear ion trap with electron transfer dissociation. The mass spectrometric instrumentation that we plan to acquire represents a true breakthrough in technology, and will be the first of its kind in operation in Australia. The instrument to be purchased will improve the ability of a wide cross section of researchers to characterize compounds important in fields as varied as medical research, agricultural biotechnology, and natural product characterization. All types of chemical research, from fundamental to applied, will benefit from access to this system, which has clearly positive implications with regard to societal impact. Implementing this type of frontier technology is an essential step in maintaining the world class capabilities of the Australian research community.Read moreRead less
Modulation of cellular metabolism by protein and peptide peroxides. Oxidation of peptides and proteins by a wide range of reactive radicals and other oxidants, in the presence of oxygen, generates protein peroxides. These species are now recognised to be key intermediates in both the deterioration of foods (e.g. development of rancidity and off-flavours, changes in colour and texture) and a number of human diseases, including cancer, heart disease and ageing. How these peroxides cause biological ....Modulation of cellular metabolism by protein and peptide peroxides. Oxidation of peptides and proteins by a wide range of reactive radicals and other oxidants, in the presence of oxygen, generates protein peroxides. These species are now recognised to be key intermediates in both the deterioration of foods (e.g. development of rancidity and off-flavours, changes in colour and texture) and a number of human diseases, including cancer, heart disease and ageing. How these peroxides cause biological perturbations is poorly understood. The proposed studies will provide valuable information as to how these peroxides affect cellular metabolism and provide key leads as to strategies which may prevent such damage.Read moreRead less
Evolution, structure and function of key components in a molecular machine. The project will provide the basis for training of students and personnel in the previously recognized priority "Genomes-Phenomes", still the central theme of modern biology. In particular,
collaborations established with the Los Alamos National Laboratory in New Mexico will transfer to Australia expertise in the cutting edge discipline of small angle scattering for analysis of biologically important molecules. Such tr ....Evolution, structure and function of key components in a molecular machine. The project will provide the basis for training of students and personnel in the previously recognized priority "Genomes-Phenomes", still the central theme of modern biology. In particular,
collaborations established with the Los Alamos National Laboratory in New Mexico will transfer to Australia expertise in the cutting edge discipline of small angle scattering for analysis of biologically important molecules. Such training is essential for developing a future pool of skilled Australian scientists to staff and utilise the major national infrastructure developments represented by the Replacement Research Reactor and Australian Synchrotron, as outlined in the National Research Priority "Frontier Technologies".Read moreRead less
Investigating the subunit interactions of a molecular protein import machine. The project will provide fundamental knowledge of how sophisticated natural molecular machines interact with their substrates in plants and animals. It will also provide the basis for training of students and personnel in a range of structural biology technologies including several that are not commonly used by biologists, but make use of two major facilities that have been invested in by our government, namely the Aus ....Investigating the subunit interactions of a molecular protein import machine. The project will provide fundamental knowledge of how sophisticated natural molecular machines interact with their substrates in plants and animals. It will also provide the basis for training of students and personnel in a range of structural biology technologies including several that are not commonly used by biologists, but make use of two major facilities that have been invested in by our government, namely the Australian Synchrotron and the OPAL Research Reactor.Read moreRead less
Mechanistic studies on the oxidation of amino acids, peptides and proteins and its biological consequences. Exposure of amino acids and proteins to radicals, oxidants, UV light, and metal ions results in oxidation, with consequent alteration to protein structure and function. It has been shown that these reactions occur during food spoilage, exposure of plants to excess UV light, and in a number of human diseases (e.g. heart disease and cancer). Despite evidence for a key role for protein oxidat ....Mechanistic studies on the oxidation of amino acids, peptides and proteins and its biological consequences. Exposure of amino acids and proteins to radicals, oxidants, UV light, and metal ions results in oxidation, with consequent alteration to protein structure and function. It has been shown that these reactions occur during food spoilage, exposure of plants to excess UV light, and in a number of human diseases (e.g. heart disease and cancer). Despite evidence for a key role for protein oxidation in these events, the fundamental chemistry and biochemistry of protein oxidation is incompletely understood. This is addressed in this project. Knowledge of the mechanisms of these reactions is a vital pre-requisite to the rational design of preventative strategies that might enhance food quality, minimise UV damage and enhance human health.Read moreRead less
A new chemotherapeutic target from Leishmania SPP. Understanding and inhibiting CYP61LD, a sterol C22 desaturase. Leishamniasis is a debilitating and often fatal disease that is caused by a parasite, Leishmania sp., which is increasing its range to include Australia. This project aims to explore possible chemotherapeutics for the disease which inhibit a particular and unique enzyme the organism uses to synthesise the sterols it requires to live.
Streamlining the dynamin epilepsy drug pipeline. Epilepsy affects up to one percent of Australia's population, yet one in three fail to respond to current medications. Our results will greatly impact on development of future epilepsy therapy. Identification of a new target for epileptic will allow better drug design to improve the potency of our lead drugs. This holds hope that new generation drugs will be more effective. The drugs are predicted to have fewer complications and side-effects. Th ....Streamlining the dynamin epilepsy drug pipeline. Epilepsy affects up to one percent of Australia's population, yet one in three fail to respond to current medications. Our results will greatly impact on development of future epilepsy therapy. Identification of a new target for epileptic will allow better drug design to improve the potency of our lead drugs. This holds hope that new generation drugs will be more effective. The drugs are predicted to have fewer complications and side-effects. The outcome has the potential to vastly improve prospects for up to 200,000 Australians. Intellectual property (IP) retained in Australia will generate future biotechnology industry. The novel chemical biological approaches will facilitate training of future generations of Australian scientists.Read moreRead less