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
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
Harnessing the potential of metals in biocatalysis. The project aims to use an integrated, multi-disciplinary approach to study the properties of a group of related but functionally diverse enzymes; binuclear metallohydrolases (BMHs). These enzymes are of great relevance to protein engineers aiming to produce potent agents for bioremediation and pharmacologists interested in developing drugs. Elucidating and modulating the mode of action of BMHs is thus our main objective and should provide esse ....Harnessing the potential of metals in biocatalysis. The project aims to use an integrated, multi-disciplinary approach to study the properties of a group of related but functionally diverse enzymes; binuclear metallohydrolases (BMHs). These enzymes are of great relevance to protein engineers aiming to produce potent agents for bioremediation and pharmacologists interested in developing drugs. Elucidating and modulating the mode of action of BMHs is thus our main objective and should provide essential information to fully exploit the potential of these enzymes for practical applications. In particular, understanding how metal ions interact with BMHs and how this contributes to their reactivity is crucial to optimally understand their biotechnological potential.Read moreRead less
Facilitating drug synthesis, development and detection: the enzymatic synthesis of beta-glucuronides. This project will develop new catalysts to aid the development of pharmaceuticals and help fight the war against drugs.
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
Development of potent and specific modulators of the human sodium channel Nav1.7. There are few effective drugs available for the treatment of chronic pain. This team recently discovered that spider venoms are a rich source of inhibitors of Nav1.7, a new target for anti-pain drugs. The goal of this project is to develop potent blockers of Nav1.7 that can be used to critically assess the role of this ion channel in mediating pain.
Asymmetric Synthesis of Chiral Phosphines, Arsines, and Stibines. There are now chiral phosphine-transition metal catalysts that rival enzymes in their efficiency for the asymmetric synthesis of important chiral drugs, fragrants, cosmetics, nutrients, vitamins, and pesticides. This project is aimed at a generalised asymmetric synthesis of the critical components of these enzyme mimics, notably enantiopure chiral phosphines, but also chiral arsines and stibines, by a highly innovative approach t ....Asymmetric Synthesis of Chiral Phosphines, Arsines, and Stibines. There are now chiral phosphine-transition metal catalysts that rival enzymes in their efficiency for the asymmetric synthesis of important chiral drugs, fragrants, cosmetics, nutrients, vitamins, and pesticides. This project is aimed at a generalised asymmetric synthesis of the critical components of these enzyme mimics, notably enantiopure chiral phosphines, but also chiral arsines and stibines, by a highly innovative approach that involves novel six-electron phosphenium, arsenium, and stibinium cations that are themselves stabilised by chiral phosphines so that chemical breeder reactions are possible. The use of chiral auxiliaries from the natural pool and from biotechnology will also be investigated.Read moreRead less
Quantum-chemical design of stereoregular polyphosphines for nanowires. In this project we will be designing and producing stereoregular polyphosphines that can self-assemble gold and silver complexes that mimic the molecular architectures of DNA and certain proteins. The longer gold complexes will behave as insulated nanowires, and are an exciting prospect for the development of nanotechnological devices. The shorter silver and gold complexes are expected to have significant antitumour propertie ....Quantum-chemical design of stereoregular polyphosphines for nanowires. In this project we will be designing and producing stereoregular polyphosphines that can self-assemble gold and silver complexes that mimic the molecular architectures of DNA and certain proteins. The longer gold complexes will behave as insulated nanowires, and are an exciting prospect for the development of nanotechnological devices. The shorter silver and gold complexes are expected to have significant antitumour properties. This project, which will use a unique theoretical-experimental approach to design the stereoregular polyphosphines, will enhance Australia's international scientific reputation, and will contribute to technological advancement in the national priority areas of nanotechnology and biotechnology.Read moreRead less
Towards Nano-circuits: 2 and 3-Dimensional Carbon-Wired Nano-architectures. Whilst Australia has a world-class profile in organotransition metal chemistry, main-group chemistry is under-represented, despite the enormous technological importance of materials based on these elements. In addition to the fundamental breakthrough science to be explored, the project will provide a training vehicle for 5 young scientists in both main group and organometallic chemistry. The target compounds involve an e ....Towards Nano-circuits: 2 and 3-Dimensional Carbon-Wired Nano-architectures. Whilst Australia has a world-class profile in organotransition metal chemistry, main-group chemistry is under-represented, despite the enormous technological importance of materials based on these elements. In addition to the fundamental breakthrough science to be explored, the project will provide a training vehicle for 5 young scientists in both main group and organometallic chemistry. The target compounds involve an essentially unique marriage of the fields of main-group and transition metal chemistry to provide complex nano-architectures based on the modular interconnection of metals and non-metals by carbon wires at the molecular level - nanoscopic counterparts of macroscopic circuit components.Read moreRead less
Understanding and Harnessing the Unique and Curious Metal Boron Bond: Unlocking the Metallaboratrane Cage. Metal-boron bonding holds enormous technological importance due to the emergence of boron-based metal-mediated synthetic transformations that access a diversity of high value-added fine chemicals. Whilst Australia boasts an emergent boron-based fine chemicals industry, no research program into the nature of metal boron bonding exists to provide either fundamental science or advanced trainin ....Understanding and Harnessing the Unique and Curious Metal Boron Bond: Unlocking the Metallaboratrane Cage. Metal-boron bonding holds enormous technological importance due to the emergence of boron-based metal-mediated synthetic transformations that access a diversity of high value-added fine chemicals. Whilst Australia boasts an emergent boron-based fine chemicals industry, no research program into the nature of metal boron bonding exists to provide either fundamental science or advanced training in organometallic boron chemistry. The proposed work offers two distinct national benefits: The maintenance of a discipline in which Australia leads the world (metallaboratranes) and the genesis of one, which whilst intensely studied elsewhere, is notably absent from the Australian science base (low coordinate, unsaturated boron chemistry).Read moreRead less