Discovery and applications of circular proteins. The many national benefits that will flow from this program include (i) new knowledge in plant biochemistry, peptide chemistry and protein engineering protected by a strong intellectual property position that will give Australia a competitive edge in relevant biotechnology applications; (ii) the training of a new generation of skilled researchers to drive a sustainable biotechnology sector in Australia; (iii) economic benefits from royalty returns ....Discovery and applications of circular proteins. The many national benefits that will flow from this program include (i) new knowledge in plant biochemistry, peptide chemistry and protein engineering protected by a strong intellectual property position that will give Australia a competitive edge in relevant biotechnology applications; (ii) the training of a new generation of skilled researchers to drive a sustainable biotechnology sector in Australia; (iii) economic benefits from royalty returns on drugs and agricultural products that will likely arise from the program; (iv) environment benefits due to a reduced need for chemical insecticides; and (v) social benefits due to a reduction in suffering from diseases for which drugs are developed as a result of this program.Read moreRead less
Understanding the Chemical Processes Involved in the Metabolism of Peptide Hormones. Peptide hormones regulate normal physiological activity in humans, and their over-production causes diseases such as cancer. The aims of this project are: to delineate the chemical processes through which these hormones are produced; to develop inhibitors of enzymes involved in hormone production, and agonists and antagonists of receptors through which the hormones act; and to study the ability of the inhibitors ....Understanding the Chemical Processes Involved in the Metabolism of Peptide Hormones. Peptide hormones regulate normal physiological activity in humans, and their over-production causes diseases such as cancer. The aims of this project are: to delineate the chemical processes through which these hormones are produced; to develop inhibitors of enzymes involved in hormone production, and agonists and antagonists of receptors through which the hormones act; and to study the ability of the inhibitors, agonists and antagonists to override and bypass the chemical control mechanisms through which hormone levels are usually maintained at homeostasis. The research is expected to lead to a better fundamental understanding of hormone metabolism, and to underpin the basis for the development of new disease therapies.Read moreRead less
Synthetic, Molecular and Biological Studies on Novel Marine Metabolites Isolated from Great Barrier Reef Sponges. Whilst structurally remarkable marine natural products, generated via unprecedented biosynthetic pathways, continue to be isolated from organisms found on the Barrier Reef these substances remain largely unexploited in terms of both their potent biological and ecological properties. Efficient syntheses of two classes of marine metabolites will be undertaken to allow biological, biosy ....Synthetic, Molecular and Biological Studies on Novel Marine Metabolites Isolated from Great Barrier Reef Sponges. Whilst structurally remarkable marine natural products, generated via unprecedented biosynthetic pathways, continue to be isolated from organisms found on the Barrier Reef these substances remain largely unexploited in terms of both their potent biological and ecological properties. Efficient syntheses of two classes of marine metabolites will be undertaken to allow biological, biosynthetic and ecological evaluation of advanced intermediates and final products. Such evaluations will provide new insights into the therapeutic and ecological potential as well as the origins of these natural products. New agents for the management of marine ecosystems and the treatment of oncological and other diseases should emerge.Read moreRead less
The role of gamma glutamyl cyclotransferase in glutathione homeostasis. The aim of this study is to understand the structure and function of gamma-glutamyl cyclotransferase (GGCT) and its role in glutathione synthesis and turnover. Glutathione is essential for life and serves multiple biological functions protecting against oxidative stress, and aiding in the detoxification and excretion of foreign chemicals. This study will explore a new approach to changing intracellular glutathione concentra ....The role of gamma glutamyl cyclotransferase in glutathione homeostasis. The aim of this study is to understand the structure and function of gamma-glutamyl cyclotransferase (GGCT) and its role in glutathione synthesis and turnover. Glutathione is essential for life and serves multiple biological functions protecting against oxidative stress, and aiding in the detoxification and excretion of foreign chemicals. This study will explore a new approach to changing intracellular glutathione concentrations that has wide applications in the treatment of inherited enzyme deficiencies, cancer and the development of herbicide resistant crop plants. The study will also contribute to the training of scientists for the future development of the Australian biotechnology industryRead moreRead less
Total Synthesis and Biological Evaluation of Australian Sponge Metabolites. The development of functional syntheses of Australian natural products and certain analogues of ecological and therapeutic significance will emerge. Such activities will lead to the identification and evaluation of molecular entities of value in managing marine environments, reduce the need for removal of organisms from marine environments both within and outside of Australia as well as helping maintain and enhance chemi ....Total Synthesis and Biological Evaluation of Australian Sponge Metabolites. The development of functional syntheses of Australian natural products and certain analogues of ecological and therapeutic significance will emerge. Such activities will lead to the identification and evaluation of molecular entities of value in managing marine environments, reduce the need for removal of organisms from marine environments both within and outside of Australia as well as helping maintain and enhance chemical synthesis capacity within the country. The proposed studies could lead to the identification of related natural products produced by organisms on the Great Barrier Reef and that may display even more potent activities and/or complementary ecological roles.Read moreRead less
Voltage-dependent structural changes in voltage-gated sodium channels. This project aims to provide insights into the structural rearrangements experienced by Nav channels, which are key components of animal nervous systems. Voltage-gated sodium (Nav) channels initiate action potentials in excitable cells. They open in response to membrane depolarisation then rapidly inactivate. Eukaryotic Nav channels contain four unique voltage-sensor domains (VSDs) that control how the channel responds to mem ....Voltage-dependent structural changes in voltage-gated sodium channels. This project aims to provide insights into the structural rearrangements experienced by Nav channels, which are key components of animal nervous systems. Voltage-gated sodium (Nav) channels initiate action potentials in excitable cells. They open in response to membrane depolarisation then rapidly inactivate. Eukaryotic Nav channels contain four unique voltage-sensor domains (VSDs) that control how the channel responds to membrane potential changes. Recently reported crystal structures of bacterial Nav channels have greatly advanced the field, but these channels contain four identical VSDs and have different inactivation properties. Thus, much remains to be learnt about the conformational plasticity of eukaryotic Nav channel VSDs. The project plans to use animal toxins to capture eukaryotic VSDs in defined states of the gating cycle for detailed structural analysis using nuclear magnetic resonance and X-ray crystallography.Read moreRead less
Selectively targeting cancer and infectious disease with fragment-based drug discovery. Finding better compounds as starting points is one of the major challenges for drug discovery research. Fragments are small, weak binding molecules that can be upsized into drug leads with better properties when compared to starting with larger molecules. This project addresses two weaknesses of current fragment based drug discovery (FBDD) methods: first, the limitations associated with screening fragments; a ....Selectively targeting cancer and infectious disease with fragment-based drug discovery. Finding better compounds as starting points is one of the major challenges for drug discovery research. Fragments are small, weak binding molecules that can be upsized into drug leads with better properties when compared to starting with larger molecules. This project addresses two weaknesses of current fragment based drug discovery (FBDD) methods: first, the limitations associated with screening fragments; and second, the quality of commercial fragment libraries. This project anticipates that the findings will establish a commanding role for both mass spectrometry and three-dimensional fragments in advancing FBDD approaches. It also expects to identify fragments with favourable development prospects towards the next generation of therapeutics.Read moreRead less
A Tough Resilin Based Hydrogel Platform for Repair and Regeneration. This project seeks to develop novel hydrogels that mimic the properties of the body. In the field of repair and regeneration, our challenge is to make hydrogels that retain the fatigue and resilience properties of the natural body part, but are comprised of nontoxic material. Resilin is a remarkable material exhibiting a broad range of stimuli-responsive behaviour and outstanding elasticity. The project aim is to create a tough ....A Tough Resilin Based Hydrogel Platform for Repair and Regeneration. This project seeks to develop novel hydrogels that mimic the properties of the body. In the field of repair and regeneration, our challenge is to make hydrogels that retain the fatigue and resilience properties of the natural body part, but are comprised of nontoxic material. Resilin is a remarkable material exhibiting a broad range of stimuli-responsive behaviour and outstanding elasticity. The project aim is to create a tough and responsive hydrogel platform from this disordered protein family through greater understanding of structure and mechanical function and incorporating adequate stiffness, strength and biocompatibility. Such tough hydrogels would be applicable to a range of biotechnological applications (eg intervertebral disc repair or artificial skin tissue engineering).Read moreRead less
Harnessing molecular strain for drug discovery and bioconjugation. Peptides and proteins are increasingly important therapies for the treatment of disease. Nevertheless, the synthesis and optimisation of these high-value compounds still relies primarily on technologies developed decades ago. There is a desperate need for modern strategies to unlock the full potential of peptides and proteins for diverse applications in drug discovery. This interdisciplinary research aims to develop new tools for ....Harnessing molecular strain for drug discovery and bioconjugation. Peptides and proteins are increasingly important therapies for the treatment of disease. Nevertheless, the synthesis and optimisation of these high-value compounds still relies primarily on technologies developed decades ago. There is a desperate need for modern strategies to unlock the full potential of peptides and proteins for diverse applications in drug discovery. This interdisciplinary research aims to develop new tools for the construction and modification of peptides and proteins by harnessing the energy in a unique class of strained molecules. A focus on peptide-based inhibitors of the proteasome, a critical target for modern cancer treatments, should provide future health and economic benefits for the Australian community.Read moreRead less
Advances in Peptide Synthesis: Exploiting Underutilised Functional Groups. The translation of therapeutically-relevant classes of peptides to the clinic is often limited by chemists' ability to synthesise these complex biomolecules efficiently and sustainably. This project aims to develop new tools for the preparation of designer peptides that are broadly inspired by an underutilised reactive group found in naturally-occurring peptide sequences. Expected outcomes encompass health and economic be ....Advances in Peptide Synthesis: Exploiting Underutilised Functional Groups. The translation of therapeutically-relevant classes of peptides to the clinic is often limited by chemists' ability to synthesise these complex biomolecules efficiently and sustainably. This project aims to develop new tools for the preparation of designer peptides that are broadly inspired by an underutilised reactive group found in naturally-occurring peptide sequences. Expected outcomes encompass health and economic benefits for the Australian community, including: the first approach to a class of promising antibiotic peptide natural product analogues, the development of a mild electrochemical approach to peptide modification, and the production of a library of novel amino acids for incorporation into potential antibiotic leads.Read moreRead less