Total chemical synthesis of a redesigned enzyme, HIV-1 PR, containing an artificial tunable catalytic apparatus. The research project proposed represents a novel approach using total chemical synthesis to study the enzyme action of the HIV-1 PR, an aspartyl protease essential for the replication of AIDS virus. The redesign of the catalytic apparatus will allow us to investigate molecular aspects of its action. The synthetic polypeptide chain will be folded and characterised for the correct folde ....Total chemical synthesis of a redesigned enzyme, HIV-1 PR, containing an artificial tunable catalytic apparatus. The research project proposed represents a novel approach using total chemical synthesis to study the enzyme action of the HIV-1 PR, an aspartyl protease essential for the replication of AIDS virus. The redesign of the catalytic apparatus will allow us to investigate molecular aspects of its action. The synthetic polypeptide chain will be folded and characterised for the correct folded structure by NMR, and assayed for enzymatic activity. It can be expected that significant new insights into the molecular basis of the properties of the HIV-1 PR will be obtained. This will be an important contribution to biomedical research.Read moreRead less
CHARACTERISATION OF NOVEL BIOACTIVES FROM AUSTRALIAN HONEY WITH THERAPEUTIC POTENTIAL. Honey from specific Australian flowering plants has been identified that contain significant therapeutic properties in wound healing and other treatments. The research project proposed will identify and fully characterise the bioactive components of selected Australian honey (Medihoney) with antibiotic and growth promoting activites. These aims will be supported by high resolution mass spectrometry interfaced ....CHARACTERISATION OF NOVEL BIOACTIVES FROM AUSTRALIAN HONEY WITH THERAPEUTIC POTENTIAL. Honey from specific Australian flowering plants has been identified that contain significant therapeutic properties in wound healing and other treatments. The research project proposed will identify and fully characterise the bioactive components of selected Australian honey (Medihoney) with antibiotic and growth promoting activites. These aims will be supported by high resolution mass spectrometry interfaced with HPLC and or affinity chip surfaces, 750 MHz NMR analysis and a range of relevant bioassays on specific organisms and cell lines. These outcomes will not only enhance the value of current honey-based products but have the potential to identify new therapeutic lead molecules.Read moreRead less
An Integrated Approach Towards Development of Highly Specific Chemotherapeutics. Many diseases are caused or can be treated by modifying the activities of particular enzymes. Molecules that affect enzymatic activities have potential as therapeutic agents. A successful approach to the discovery of new drug molecules is to design them based on very detailed knowledge of how the target enzyme works. In this project, a highly motivated team of scientists will use state of the art instruments and the ....An Integrated Approach Towards Development of Highly Specific Chemotherapeutics. Many diseases are caused or can be treated by modifying the activities of particular enzymes. Molecules that affect enzymatic activities have potential as therapeutic agents. A successful approach to the discovery of new drug molecules is to design them based on very detailed knowledge of how the target enzyme works. In this project, a highly motivated team of scientists will use state of the art instruments and their combined creativity to understand the intimate details of how one large group of enzymes work. The enzymes selected are the bimetallic hydrolases, many of which are associated with disorders including osteoporosis, mental illnesses, cystic fibrosis and various types of cancer.Read moreRead less
Chemical Insights to Peptide Helix-Sheet-Nanofibre Equilibria. We live in an ageing community that is experiencing exponential growth in neurological diseases that require full time carers and place significant burdens on our health system. Many such diseases are caused by (apparently) abnormal folding of proteins that aggregate into insoluble materials. The chemistry behind these processes is not sufficiently well understood to know precisely why the diseases are caused and how they might be tr ....Chemical Insights to Peptide Helix-Sheet-Nanofibre Equilibria. We live in an ageing community that is experiencing exponential growth in neurological diseases that require full time carers and place significant burdens on our health system. Many such diseases are caused by (apparently) abnormal folding of proteins that aggregate into insoluble materials. The chemistry behind these processes is not sufficiently well understood to know precisely why the diseases are caused and how they might be treated. This project will use new strategies to control peptide folding, provide important new information relevant to understanding such processes/diseases, and teach us how to engineer important new biomaterials that can advance nanotechnology. Read moreRead less
Disruption of Sex Pheromone Biosynthesis: A Novel Control Method for Pestiferous Fruit Flies by. Fruit flies from the genus Bactrocera are economically important worldwide. B. tryoni, (Queensland fruit fly) is the most damaging horticultural pest in Australia and B. oleae (olive fly) is a major European pest. These flies use chemicals of similar but distinct structure for communication and particularly for finding mates. This research will examine the pathways and enzymes these flies use to sy ....Disruption of Sex Pheromone Biosynthesis: A Novel Control Method for Pestiferous Fruit Flies by. Fruit flies from the genus Bactrocera are economically important worldwide. B. tryoni, (Queensland fruit fly) is the most damaging horticultural pest in Australia and B. oleae (olive fly) is a major European pest. These flies use chemicals of similar but distinct structure for communication and particularly for finding mates. This research will examine the pathways and enzymes these flies use to synthesise sex pheromones. We propose that understanding the chemical and biochemical steps employed by the flies will allow us to design inhibitors to prevent pheromone production and thus provide a novel, species specific method for controlling fruit flies.Read moreRead less
Covalent Hydrogen Bond Mimetics of Helical Peptide Hormones. Peptide hormones have been identified that adopt a helical shape when bound to their receptor. The project will produce new versions of these hormones by the use of directly bonded chemical linkers in place of the relatively weak helix hydrogen bonds. The resulting hormone mimics will be more stable, have lower molecular weight and be more selective than the natural hormones making them more suitable as drugs. Our new chemical techn ....Covalent Hydrogen Bond Mimetics of Helical Peptide Hormones. Peptide hormones have been identified that adopt a helical shape when bound to their receptor. The project will produce new versions of these hormones by the use of directly bonded chemical linkers in place of the relatively weak helix hydrogen bonds. The resulting hormone mimics will be more stable, have lower molecular weight and be more selective than the natural hormones making them more suitable as drugs. Our new chemical techniques allow us for the first time to fully investigate this approach which if successful will be applicable to many other helical peptides and therefore could be an important drug development technique.Read moreRead less
High throughput engineering of genetically encodable fluorescent sensors of intracellular signalling networks. Understanding of biochemical processes in living organisms is central to biological research and drug discovery. At present, the field suffers from a chronic paucity of adequate observation methods. The proposed project represents an interdisciplinary effort to create approaches for real-time monitoring of complex cellular chemistries. This work will deliver novel technologies for use i ....High throughput engineering of genetically encodable fluorescent sensors of intracellular signalling networks. Understanding of biochemical processes in living organisms is central to biological research and drug discovery. At present, the field suffers from a chronic paucity of adequate observation methods. The proposed project represents an interdisciplinary effort to create approaches for real-time monitoring of complex cellular chemistries. This work will deliver novel technologies for use in diagnostics and drug development. It will provide vital information on the changes in cellular processes induced by malignant transformation, viral infection and aging. This work will generate both health and economic benefits for the community and have a positive impact on the international visibility of Australian biomedical research.Read moreRead less
Design and discovery of novel conotoxins that target ion channels and receptors. The national benefits that may arise include (i) new knowledge of biologically active peptides and their mode of action that will be protected through patent applications and provide a competitive edge for Australian biotechnology (ii) the training of a new generation of skilled researchers in chemical and structural biology that will sustain the biotechnology industry (iii) economic benefits from licensing and roya ....Design and discovery of novel conotoxins that target ion channels and receptors. The national benefits that may arise include (i) new knowledge of biologically active peptides and their mode of action that will be protected through patent applications and provide a competitive edge for Australian biotechnology (ii) the training of a new generation of skilled researchers in chemical and structural biology that will sustain the biotechnology industry (iii) economic benefits from licensing and royalty returns on drug leads that may arise from this program (iv) environmental benefits from the development of more sensitive analytical methods that obviate over collection of endangered species and (v) social benefits from a reduction in suffering from diseases for which drugs are developed as a result of this program.Read moreRead less
Electrochemically Driven Molybdoenzyme Catalysis. Enzymes that catalyse oxidation and reduction reactions need to exchange electrons with their substrate and this supply of electrons needs to be sustained. Artificially reconstituted systems can be developed where the enzyme is coupled with an electrode and the current (electrons) exchanged during the reaction are measured directly. In this project we will reveal whether some unusual and unexplained electrochemical phenomena seen before are relat ....Electrochemically Driven Molybdoenzyme Catalysis. Enzymes that catalyse oxidation and reduction reactions need to exchange electrons with their substrate and this supply of electrons needs to be sustained. Artificially reconstituted systems can be developed where the enzyme is coupled with an electrode and the current (electrons) exchanged during the reaction are measured directly. In this project we will reveal whether some unusual and unexplained electrochemical phenomena seen before are related to the properties of the enzymes themselves or the ways in which their experiments have been conducted.Read moreRead less
Mechanistic Studies of Dimethylsulfide Dehydrogenase: A Novel Bacterial Molybdoenzyme. The aim of this proposal is to use electrochemical, spectroscopic and molecular biological techniques to understand the mechanism of action of the enzyme dimethylsulfide dehydrogenase. This enzyme is representative of an major group of molybdenum-containing enzymes that have importance in microbial biotransformations. The project will provide fundamental information about a multi-redox centre protein that has ....Mechanistic Studies of Dimethylsulfide Dehydrogenase: A Novel Bacterial Molybdoenzyme. The aim of this proposal is to use electrochemical, spectroscopic and molecular biological techniques to understand the mechanism of action of the enzyme dimethylsulfide dehydrogenase. This enzyme is representative of an major group of molybdenum-containing enzymes that have importance in microbial biotransformations. The project will provide fundamental information about a multi-redox centre protein that has potential application in biosensors and biocatalysis.Read moreRead less