Understanding and exploiting bacterial sulfatases. Bacterial sulfatases participate in environmental nutrient cycling and are implicated in bacterial pathogenesis mechanisms. These enzymes catalyze the hydrolysis of sulfate esters and possess an unusual posttranslational active-site modification where a cysteine residue is oxidized to formylglycine. We will study the mechanism of these enzymes in detail and design inhibitors that exploit the reactivity of this aminoacid. This work has significan ....Understanding and exploiting bacterial sulfatases. Bacterial sulfatases participate in environmental nutrient cycling and are implicated in bacterial pathogenesis mechanisms. These enzymes catalyze the hydrolysis of sulfate esters and possess an unusual posttranslational active-site modification where a cysteine residue is oxidized to formylglycine. We will study the mechanism of these enzymes in detail and design inhibitors that exploit the reactivity of this aminoacid. This work has significance because of application to areas that include the treatment of cancer and bacterial infections. Additionally, we will clone novel carbohydrate sulfatases from the heparin-degrading bacterium Flavobacterium heparinum. These sulfatases will have use in biotechnology for characterization of sulfated glycoconjugates.Read moreRead less
Re-purposing shelved 'antibiotics' in the search for new herbicides. This project aims to identify target-specific herbicidal compounds that inhibit amino acid biosynthesis pathways to tackle herbicide resistance. This project expects to validate a novel herbicide discovery strategy by exploiting the similarity between bacterial and plant enzymes in these pathways to re-purpose failed 'antibiotics'. Expected outcomes include advances in our knowledge of the structure, function and inhibition of ....Re-purposing shelved 'antibiotics' in the search for new herbicides. This project aims to identify target-specific herbicidal compounds that inhibit amino acid biosynthesis pathways to tackle herbicide resistance. This project expects to validate a novel herbicide discovery strategy by exploiting the similarity between bacterial and plant enzymes in these pathways to re-purpose failed 'antibiotics'. Expected outcomes include advances in our knowledge of the structure, function and inhibition of novel herbicide targets, and the identification of compounds with herbicidal activity. This should lay the foundations for long-term benefits related to improving the quantity and quality of Australia’s crops to ensure our food security.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE190100806
Funder
Australian Research Council
Funding Amount
$419,854.00
Summary
Towards herbicide cocktails with a new mode of action to avert resistance. This project aims to target herbicide resistant weeds which represent one of the largest threats to Australian and global food security. Targeting of unexplored pathways in plants to develop a novel herbicide strategy is expected to be achieved, and will include the structural and functional characterisation of key enzymes in these pathways. This project is expected to provide significant benefits for effective weed manag ....Towards herbicide cocktails with a new mode of action to avert resistance. This project aims to target herbicide resistant weeds which represent one of the largest threats to Australian and global food security. Targeting of unexplored pathways in plants to develop a novel herbicide strategy is expected to be achieved, and will include the structural and functional characterisation of key enzymes in these pathways. This project is expected to provide significant benefits for effective weed management to sustain Australia’s agricultural industry through enhanced food production from increased crop yields, whilst ensuring food security. These outcomes, coupled with decades of over-reliance on current herbicides, means there has never been a greater need for new and effective herbicides.Read moreRead less
Functional evolution and therapeutic potential of snake venom coagulotoxins. This project aims to identify and understand the factors that influence the useful function of key residues (parts of larger compounds) in Australian snake venom coagulotoxins, which alter blood-clotting ability. In recent years, snake venom compounds have been demonstrated as useful models from which to synthesise therapeutic drugs to improve health and well-being. This project will test these important toxins on model ....Functional evolution and therapeutic potential of snake venom coagulotoxins. This project aims to identify and understand the factors that influence the useful function of key residues (parts of larger compounds) in Australian snake venom coagulotoxins, which alter blood-clotting ability. In recent years, snake venom compounds have been demonstrated as useful models from which to synthesise therapeutic drugs to improve health and well-being. This project will test these important toxins on model systems that represent natural prey items in order to determine the molecular and functional evolution of blood-clot forming enzymes. Expected outcomes include substantial contributions to the body of evolutionary biology knowledge, as well as narrowing the search for the ultimate drug candidates.Read moreRead less
Development Of Purine Nucleoside Phosphonates As Anti-malarial Drugs Targeting Nuceloside Synthesis In Plasmodium
Funder
National Health and Medical Research Council
Funding Amount
$428,917.00
Summary
Malaria is one of the most serious infectious diseases today. Because of its location in a malaria endemic region, the tropical regions (above 19 S in latitude) of Australia face an emerging threat. The causative agent of the disease is the parasite, Plasmodium. Because of increasing resistance to existing medicines, new drugs are now needed. The drugs we will develop target the parasites replication cycle and are related in structure to those in use to treat viral infections including AIDS.
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
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
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
Australian Laureate Fellowships - Grant ID: FL140100027
Funder
Australian Research Council
Funding Amount
$2,898,150.00
Summary
Under the hood: single-molecule studies of multi-protein machines. Under the hood: single-molecule studies of multi-protein machines. Living cells are filled with complex protein machines that are responsible for the molecular processes supporting life. This project is aimed towards the development of physical tools that enable the study of these protein complexes at the level of single molecules. This project aims to study the protein machinery responsible for DNA replication, the process of du ....Under the hood: single-molecule studies of multi-protein machines. Under the hood: single-molecule studies of multi-protein machines. Living cells are filled with complex protein machines that are responsible for the molecular processes supporting life. This project is aimed towards the development of physical tools that enable the study of these protein complexes at the level of single molecules. This project aims to study the protein machinery responsible for DNA replication, the process of duplicating genomic information before cell division. By making real-time single-molecule movies of the replication process, this project aims to unravel the molecular mechanisms of this important process and provide the knowledge required to understand disease mechanisms and catalyse drug development.Read moreRead less
Virtual Screening In Structure-Based Drug Design For Malaria
Funder
National Health and Medical Research Council
Funding Amount
$285,000.00
Summary
Malaria continues to be one of the most serious health problems in the world today with approximately 300 million people affected and 1.5 million recorded deaths per year. The most deadly and widespread parasite responsible for this disease is Plasmodium falciparum. Because of the parasite's increasing resistance to traditional medication, there is an urgent need to develop more effective treatments. Two approaches are feasible: vaccines and new drugs. Both will probably be necessary to combat t ....Malaria continues to be one of the most serious health problems in the world today with approximately 300 million people affected and 1.5 million recorded deaths per year. The most deadly and widespread parasite responsible for this disease is Plasmodium falciparum. Because of the parasite's increasing resistance to traditional medication, there is an urgent need to develop more effective treatments. Two approaches are feasible: vaccines and new drugs. Both will probably be necessary to combat the spread and consequences of malaria. We are approaching this problem by targeting an enzyme which is essential for the survival of the parasite. All protozoan parasites make their purine nucleotides (the building blocks of DNA and RNA) by purine base salvage. Unlike humans, they cannot make purines from simple precursor molecules. The key enzyme in the salvage pathway is hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT). Our plan is to capitalize on knowledge of the precise structure of HGXPRT and the increased power of computers to determine which chemicals are able to bind tightly and specifically to the active site of the enzyme. We will then test the ability of these compounds to inhibit purified human and Plasmodium enzymes and their ability to inhibit the growth of the malarial parasite in red cells. Chemical synthesis will be used to improve the effectiveness of these compounds.Read moreRead less