Chemical staples and chemical probes to dissect dynamins cellular roles. Modulation of protein structure drives cellular function. Dynamin GTPase forms at least two macromolecular structures with different cellular functions. The drivers behind these different structures is unknown. In this project we will leverage our discoveries, and planned enhancements, of chemical biology probes that will modulate dynamin activity by inhibiting at three distinct sites, and one site that stimulates dynamin a ....Chemical staples and chemical probes to dissect dynamins cellular roles. Modulation of protein structure drives cellular function. Dynamin GTPase forms at least two macromolecular structures with different cellular functions. The drivers behind these different structures is unknown. In this project we will leverage our discoveries, and planned enhancements, of chemical biology probes that will modulate dynamin activity by inhibiting at three distinct sites, and one site that stimulates dynamin activity. It is known that Dynamin helices and rings are believed responsible for at least three in cell biological functions: in hormone, neutral and receptor internalisation; cellular mitosis and in actin dynamics. Prior to this work we have lacked the tools to understand the role of shape modulation of protein function.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
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
Unlocking the secret chemistry of organosulfur biodegradation. The element sulfur is essential for life. Its transformation between organic-sulfur compounds to inorganic forms is a crucial part of the biogeochemical cycle. This project will elucidate the molecular details of the final leg of the biosulfur cycle: organosulfur breakdown into mineral form. An integrated chemical and biochemical approach will be used to illuminate how the carbon-sulfur bond is broken. This project will deliver a det ....Unlocking the secret chemistry of organosulfur biodegradation. The element sulfur is essential for life. Its transformation between organic-sulfur compounds to inorganic forms is a crucial part of the biogeochemical cycle. This project will elucidate the molecular details of the final leg of the biosulfur cycle: organosulfur breakdown into mineral form. An integrated chemical and biochemical approach will be used to illuminate how the carbon-sulfur bond is broken. This project will deliver a detailed molecular understanding of organosulfur breakdown to permit organosulfur recycling. Benefits of this research include potential biotechnology applications for breaking down xenobiotic organosulfonates and sustainable approaches to reduce dependence on agricultural fertilisers.Read moreRead less
Investigations into the antibacterial mechanism of action of cannabidiol. Cannabidiol (CBD) comes from a set of naturally occurring compounds, with a range of applications in mainstream culture. We have recently reported that CBD has excellent antimicrobial properties, with the ability to kill bacteria. This project aims to understand how CBD works by examining CBD-bacterial interactions at a genetic and molecular level. By understanding how CBD acts on and within bacterial cells, we can create ....Investigations into the antibacterial mechanism of action of cannabidiol. Cannabidiol (CBD) comes from a set of naturally occurring compounds, with a range of applications in mainstream culture. We have recently reported that CBD has excellent antimicrobial properties, with the ability to kill bacteria. This project aims to understand how CBD works by examining CBD-bacterial interactions at a genetic and molecular level. By understanding how CBD acts on and within bacterial cells, we can create fundamental new knowledge that could lead to the design of improved analogs of CBD to that can treat bacterial infections. As a much-needed completely new antibiotic class, this will lead to significant benefits, supporting Australia's National Strategy to combat the challenges posed by antimicrobial resistance.Read moreRead less
Defining a new family of sodium channel accessory proteins. Voltage-gated sodium channels are key proteins that function as multi-subunit complexes to regulate neuronal excitability. The project aims to investigate the structure and function of a novel family of accessory subunits by utilizing a class of toxins, derived from the giant Australian stinging tree, that directly binds to these proteins to modulate sodium channel function. The project aims to generate significant new knowledge on the ....Defining a new family of sodium channel accessory proteins. Voltage-gated sodium channels are key proteins that function as multi-subunit complexes to regulate neuronal excitability. The project aims to investigate the structure and function of a novel family of accessory subunits by utilizing a class of toxins, derived from the giant Australian stinging tree, that directly binds to these proteins to modulate sodium channel function. The project aims to generate significant new knowledge on the function of sodium channels as multi-protein complexes. Expected outcomes of this project include development of novel channel-modulating molecules that may have applications as neuroscience tools to address fundamental questions about ion channel function and biology.Read moreRead less
How lipid binding proteins shape the activity of nuclear hormone receptors. This project aims to explore how a family of lipid binding proteins control organ specific activation of nuclear receptors – receptors that play a key role in generating energy and are critical for life. The project will employ chemical, molecular, cell biology approaches to generate new knowledge about lipid binding protein-receptor interactions and how these complexes dictate receptor activation. The outcomes could pro ....How lipid binding proteins shape the activity of nuclear hormone receptors. This project aims to explore how a family of lipid binding proteins control organ specific activation of nuclear receptors – receptors that play a key role in generating energy and are critical for life. The project will employ chemical, molecular, cell biology approaches to generate new knowledge about lipid binding protein-receptor interactions and how these complexes dictate receptor activation. The outcomes could provide a roadmap to design drugs that interact with the right protein in the right tissue and in doing so dramatically enhance drug specificity. This will benefit the success of drug treatments which require stimulation of a therapeutic response at a target site, and avoidance of potentially toxic activity at other locations.Read moreRead less