New Protocols for the Chemical Synthesis of Biologically Relevant Systems. Enzyme- and metal-catalysed processes will be developed and exploited for the purpose of establishing concise syntheses of biologically active and otherwise inaccessible natural products and their analogues. The range of structures to be targeted is structurally diverse and these have the potential to act as agrochemicals and/or as therapeutic agents for the treatment of a range of disease states in mammals including bact ....New Protocols for the Chemical Synthesis of Biologically Relevant Systems. Enzyme- and metal-catalysed processes will be developed and exploited for the purpose of establishing concise syntheses of biologically active and otherwise inaccessible natural products and their analogues. The range of structures to be targeted is structurally diverse and these have the potential to act as agrochemicals and/or as therapeutic agents for the treatment of a range of disease states in mammals including bacterial and viral infections, neuro-degenerative conditions and impaired cognitive function. Anti-angiogenic compounds that control otherwise unregulated cellular growth may also arise from these studies. The generation of new, homochiral metabolites for use in chemoenzymatic synthesis should also emerge from this project.Read moreRead less
Harnessing strain for chemical synthesis: The cyclopropane angle. This project aims to develop new reaction pathways of cyclopropanes, the smallest and most strained monocyclic ring systems, but which are also stable and easily prepared. Cyclopropanes have unique capacities to serve as highly effective building blocks in the synthesis of a wide range of otherwise difficult to access and biologically active molecular frameworks. This project will use cyclopropanes to rapidly assemble biologically ....Harnessing strain for chemical synthesis: The cyclopropane angle. This project aims to develop new reaction pathways of cyclopropanes, the smallest and most strained monocyclic ring systems, but which are also stable and easily prepared. Cyclopropanes have unique capacities to serve as highly effective building blocks in the synthesis of a wide range of otherwise difficult to access and biologically active molecular frameworks. This project will use cyclopropanes to rapidly assemble biologically active systems, especially pharmaceutically or agrochemically valuable natural products and relevant analogues.Read moreRead less
Enabling Methodologies for the Synthesis of Biologically Active Compounds. This project seeks to establish flexible methods of chemical synthesis for creating new molecular scaffolds capable of achieving selective enzyme inhibition. The approach aims to exploit the vast and biologically-programmed structural diversity associated with natural products. Unique, small molecule organic compounds will be obtained that reveal details of the operation of key enzymes in bacterial and mammalian systems. ....Enabling Methodologies for the Synthesis of Biologically Active Compounds. This project seeks to establish flexible methods of chemical synthesis for creating new molecular scaffolds capable of achieving selective enzyme inhibition. The approach aims to exploit the vast and biologically-programmed structural diversity associated with natural products. Unique, small molecule organic compounds will be obtained that reveal details of the operation of key enzymes in bacterial and mammalian systems. Such new knowledge would allow for the design of highly selective therapeutic agents relevant to the treatment of a range of diseases including bacterial infections, diabetes and cancer. The high-end scientific training and privileged forms of matter arising from this work would provide major benefit to the biotech sector.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE170101438
Funder
Australian Research Council
Funding Amount
$360,000.00
Summary
Application of boronate ester-appended scaffolds in drug-discovery. This project aims to improve carbohydrate synthesis. Glycochemistry is an increasingly important chemical science that combines organic synthesis with biology. This project will develop methodologies that incorporate boronate ester residues onto selected carbons of monosaccharides and transform them to obtain hitherto inaccessible scaffolds for drug discovery. This strategy can be used in the controlled assembly of other biologi ....Application of boronate ester-appended scaffolds in drug-discovery. This project aims to improve carbohydrate synthesis. Glycochemistry is an increasingly important chemical science that combines organic synthesis with biology. This project will develop methodologies that incorporate boronate ester residues onto selected carbons of monosaccharides and transform them to obtain hitherto inaccessible scaffolds for drug discovery. This strategy can be used in the controlled assembly of other biologically important compounds, including azacycles, oxacycles and inositols. The methods for the controlled diversification of carbohydrates are expected to be broadly applicable to scientific endeavours ranging from glycobiology to medicine. Successful execution will provide new drug-discovery tools and ensure Australia secures a competitive position in this rapidly expanding discipline.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
Synthesis and Biological Evaluation of Australian Sponge Metabolites. The development of concise and flexible syntheses of Australian marine natural products and analogues of ecological/therapeutic significance will emerge. Such activities will lead to the identification and evaluation of molecular entities of value in managing marine environments and help to enhance chemical synthesis capacity in Australia.
The hidden secondary metabolite biosynthetic potential of fungi. This proposal aims to develop synthetic biology tools to allow rapid access to the hidden metabolites encoded in fungal genomes and discover how they interact with plant and animal hosts. Genome sequencing reveals that fungi harbour vast hidden potential for biosynthesis of bioactive small molecules. The lack of tools to efficiently access this hidden potential has hindered the ability to develop this uncharted chemical diversity f ....The hidden secondary metabolite biosynthetic potential of fungi. This proposal aims to develop synthetic biology tools to allow rapid access to the hidden metabolites encoded in fungal genomes and discover how they interact with plant and animal hosts. Genome sequencing reveals that fungi harbour vast hidden potential for biosynthesis of bioactive small molecules. The lack of tools to efficiently access this hidden potential has hindered the ability to develop this uncharted chemical diversity for pharmaceutics and agriculture, and understand their biological roles in pathogens. Expected outcomes include sources of bioactive molecules and better management of fungal diseases in crops and humans.Read moreRead less