Mixing the jigsaw pieces of natural products: new molecules-new properties. This project aims to examine the capacity of exploiting the bacterial biosynthetic machinery to fast-track access to analogues of natural products. Due to increased drug resistance, new reservoirs of natural products are needed for evaluation as future drugs. Desferrioxamine B will be used as a model natural product to establish the biosynthesis of new analogues in bacterial culture supplemented with unsaturated, fluorin ....Mixing the jigsaw pieces of natural products: new molecules-new properties. This project aims to examine the capacity of exploiting the bacterial biosynthetic machinery to fast-track access to analogues of natural products. Due to increased drug resistance, new reservoirs of natural products are needed for evaluation as future drugs. Desferrioxamine B will be used as a model natural product to establish the biosynthesis of new analogues in bacterial culture supplemented with unsaturated, fluorinated or deuterated building blocks. The intended outcomes are to deliver advances in methods for generating structurally diverse pools of natural products, new label-free probes, knowledge of natural product biosynthesis, and excellence in training research students in frontier methods in chemical biology and drug discovery.Read moreRead less
Developing a multicomponent platform for targeted gene delivery. Gene delivery systems are important tools in biological research and offer many exciting future prospects. Delivering gene material is very difficult in practice: rapid deterioration, poor cell uptake, and reaching the right tissue and cell types are major obstacles. Ways to overcome each barrier individually have been suggested in existing research but these components have not yet been combined in a single solution, which this pr ....Developing a multicomponent platform for targeted gene delivery. Gene delivery systems are important tools in biological research and offer many exciting future prospects. Delivering gene material is very difficult in practice: rapid deterioration, poor cell uptake, and reaching the right tissue and cell types are major obstacles. Ways to overcome each barrier individually have been suggested in existing research but these components have not yet been combined in a single solution, which this project will tackle. This proposal aims to create a technology to stabilise and deliver active gene material to target cells. The gene delivery tool developed in this project will advance biological research greatly with many potential future applications.Read moreRead less
Chemical probes to dissect the cell cycle of globally important parasites . This project aims to develop new reagents, called chemical probes, to visualise key biological events in globally important pathogens. We will use innovative chemistry to modify the building blocks of DNA and provide researchers with essential tools to 'see' DNA synthesis in order to study growth and replication of pathogens in combination with microscopy. This project expects to support a major technical advance that wi ....Chemical probes to dissect the cell cycle of globally important parasites . This project aims to develop new reagents, called chemical probes, to visualise key biological events in globally important pathogens. We will use innovative chemistry to modify the building blocks of DNA and provide researchers with essential tools to 'see' DNA synthesis in order to study growth and replication of pathogens in combination with microscopy. This project expects to support a major technical advance that will address important gaps in our understanding of many pathogens (e.g. those that cause malaria and tuberculosis), at both the cellular and molecular levels. This should provide significant benefits by enabling researchers worldwide to identify new intervention opportunities that target unique aspects of pathogen biology.Read moreRead less
Venom-derived blood-brain-barrier shuttles. This project aims to discover new venom peptides capable of crossing the blood-brain barrier and to develop non-toxic peptide-based brain delivery systems. It addresses long-standing challenges and knowledge gaps in the delivery of macromolecules across biological barriers. Expected outcomes include an improved understanding of the strategies nature exploits to reach targets in the brain, mechanistic pathways to cross biological membranes, and innovati ....Venom-derived blood-brain-barrier shuttles. This project aims to discover new venom peptides capable of crossing the blood-brain barrier and to develop non-toxic peptide-based brain delivery systems. It addresses long-standing challenges and knowledge gaps in the delivery of macromolecules across biological barriers. Expected outcomes include an improved understanding of the strategies nature exploits to reach targets in the brain, mechanistic pathways to cross biological membranes, and innovative discovery and chemistry strategies to advance fundamental research across the chemical and biological sciences. Anticipated benefits include technological innovations relevant to Australia’s biotechnology sector and enhanced capacity for cross-disciplinary collaboration.Read moreRead less
Expanding access to modified proteins via a novel semi-synthetic platform. This project aims to address a critical knowledge gap in understanding how post-translational modifications modulate the structure and activity of proteins. By developing an innovative semi-synthetic platform to produce pure proteins inaccessible by existing methods, the project will reveal how natural protein modifications influence structure and function. Expected outcomes include the delivery of breakthrough technologi ....Expanding access to modified proteins via a novel semi-synthetic platform. This project aims to address a critical knowledge gap in understanding how post-translational modifications modulate the structure and activity of proteins. By developing an innovative semi-synthetic platform to produce pure proteins inaccessible by existing methods, the project will reveal how natural protein modifications influence structure and function. Expected outcomes include the delivery of breakthrough technologies for accessing modified proteins for a range of applications in academia and industry, as well as the generation of new knowledge in the fields of chemistry and biology. The project will lead to the training of interdisciplinary early career researchers and has the potential to benefit Australia’s biotechnology sector.Read moreRead less
Conotoxin diversification and evolution of venom peptides in cone snails. The marine snails of the genus Conus have evolved one of the most complex venoms that has emerged as a rich source of novel bioactive peptides. However, < 0.1% of their true potential has been characterised to-date. Using advanced genomic, proteomic, structural and pharmacological approaches pioneered in our laboratory, this study will decipher how conotoxin diversification from ancestral worm hunters facilitated the shift ....Conotoxin diversification and evolution of venom peptides in cone snails. The marine snails of the genus Conus have evolved one of the most complex venoms that has emerged as a rich source of novel bioactive peptides. However, < 0.1% of their true potential has been characterised to-date. Using advanced genomic, proteomic, structural and pharmacological approaches pioneered in our laboratory, this study will decipher how conotoxin diversification from ancestral worm hunters facilitated the shift in diet to modern fish and mollusc hunting species by determining the evolutionary trajectories of positively selected conotoxins. Investigation of the structure and function of these highly optimised venom peptides will provide new research tools and potential leads to new pharmaceuticals and agrochemicals.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
Aquatic chemo-modulators: a novel source for potent molecular probes. This project aims to investigate peptides that modulate prey behaviour. Chemical signalling constitutes much of the language of life underwater. Certain cone snails evolved a hunting strategy, where they release potent peptides to modulate fish behaviour through yet unknown mechanisms. The snail then expands its mouth and eats the fish without resistance. This project will investigate the mechanisms at play using transcriptomi ....Aquatic chemo-modulators: a novel source for potent molecular probes. This project aims to investigate peptides that modulate prey behaviour. Chemical signalling constitutes much of the language of life underwater. Certain cone snails evolved a hunting strategy, where they release potent peptides to modulate fish behaviour through yet unknown mechanisms. The snail then expands its mouth and eats the fish without resistance. This project will investigate the mechanisms at play using transcriptomics, proteomics, peptide synthesis, behavioural pharmacology and nuclear magnetic resonance. This will advance the knowledge of aquatic chemo-modulators on a functional, structural and evolutionary level, and provide a source of molecular probes with unique pharmacology and applications in human physiology, developmental biology and aquacultures.Read moreRead less
Sulfoxide Polymers - A New Paradigm in Polymer Design. Low fouling polymers are important for moderating interactions of molecules and particles with cells. In pharmaceutical sciences they are essential tools for extending the pharmacokinetics of dissolved drugs. However, the widely-used low-fouling polymer, poly(ethylene glycol) (PEG) has been recently reported to induce formation of anti-PEG antibodies. Polymeric alternatives to PEG are thus desperately needed. We introduce in this project sup ....Sulfoxide Polymers - A New Paradigm in Polymer Design. Low fouling polymers are important for moderating interactions of molecules and particles with cells. In pharmaceutical sciences they are essential tools for extending the pharmacokinetics of dissolved drugs. However, the widely-used low-fouling polymer, poly(ethylene glycol) (PEG) has been recently reported to induce formation of anti-PEG antibodies. Polymeric alternatives to PEG are thus desperately needed. We introduce in this project super-hydrophilic polymers incorporating sulfoxide groups, mimics of the polar solvent DMSO. The project aims to explore how polymer architecture can enhance biocompatibility and reduce biofouling. The outcome will be a new class of low-fouling polymeric materials with broad application in the biosciences.Read moreRead less