Discovery and characterisation of novel spider-venom peptides targeting the human sodium ion channel Nav1.7. Drugs that selectively block the human sodium ion channel Nav1.7 are likely to be powerful analgesics for treating a wide variety of pain conditions. However, it has proved difficult to obtain selective blockers of this channel. The aim of this project is to determine whether spider-venoms might provide a source of highly selective Nav1.7 blockers.
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
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
Discovery Early Career Researcher Award - Grant ID: DE180100092
Funder
Australian Research Council
Funding Amount
$418,107.00
Summary
A radical approach to unnatural amino acids and peptide-based antibiotics. This project aims to develop a new synthetic approach to valuable amino acid derivatives and their rapid incorporation into peptide analogues, including promising new antibiotic candidates. This project expects to generate knowledge in the chemical and biological sciences and build scientific capacity to address the global rise of antimicrobial resistance. It is anticipated that this will provide direct health and economi ....A radical approach to unnatural amino acids and peptide-based antibiotics. This project aims to develop a new synthetic approach to valuable amino acid derivatives and their rapid incorporation into peptide analogues, including promising new antibiotic candidates. This project expects to generate knowledge in the chemical and biological sciences and build scientific capacity to address the global rise of antimicrobial resistance. It is anticipated that this will provide direct health and economic benefits by establishing a powerful platform for peptide drug design.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.
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE200100190
Funder
Australian Research Council
Funding Amount
$620,000.00
Summary
Electrophysiology Platform for Ion-channel Characterisation. Ion channels are ubiquitous pore-forming membrane proteins, with the human genome encoding >300 ion channels. The diverse roles of ion channels include action potential generation, control of ion flow across secretory and epithelial cells, and regulation of cell volume, motility and proliferation. Pharmacological modulators are powerful tools for probing ion channel function, but for most channels these tools are lacking. Thus, this p .... Electrophysiology Platform for Ion-channel Characterisation. Ion channels are ubiquitous pore-forming membrane proteins, with the human genome encoding >300 ion channels. The diverse roles of ion channels include action potential generation, control of ion flow across secretory and epithelial cells, and regulation of cell volume, motility and proliferation. Pharmacological modulators are powerful tools for probing ion channel function, but for most channels these tools are lacking. Thus, this project aims to develop the first comprehensive toolbox of ion channel modulators using an integrated in vitro/in vivo electrophysiology platform. These pharmacological tools will be made freely available to the Australian research community for probing the mechanism and physiological function of ion channels.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE170100192
Funder
Australian Research Council
Funding Amount
$450,000.00
Summary
Deep Protein Sequencing, Structure and Quantification Facility. This project aims to establish state-of-the-art complementary mass spectrometers to help research into molecular structure and interactions, post-translational modifications, compound stability and availability within complex biological samples. The facility’s complementary mass spectrometers combine high specificity with high sensitivity and ultrafast scanning, and are expected to rapidly discover, identify and characterise biomole ....Deep Protein Sequencing, Structure and Quantification Facility. This project aims to establish state-of-the-art complementary mass spectrometers to help research into molecular structure and interactions, post-translational modifications, compound stability and availability within complex biological samples. The facility’s complementary mass spectrometers combine high specificity with high sensitivity and ultrafast scanning, and are expected to rapidly discover, identify and characterise biomolecules including peptides, proteins and small molecules. The discovery of unknown compounds is expected to improve fundamental understanding of molecular structure and function, provide opportunities for new bio-industries in health and the environment, and generate commercial opportunities through spin-off companies, patents and licensing.Read moreRead less