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
Resurrecting Ancient Proteins to Unlock New Catalytic Activity. This project aims to study the proteins that nature uses to make penicillin and related antibiotics, and their prehistoric ancestors. By doing so, the project expects to deepen understanding of these important processes, open up ways to make new antibiotics, and generate new knowledge about protein evolution. Intended outcomes include new biocatalysts based on the ancient ones, new antibiotic compounds active against resistant bacte ....Resurrecting Ancient Proteins to Unlock New Catalytic Activity. This project aims to study the proteins that nature uses to make penicillin and related antibiotics, and their prehistoric ancestors. By doing so, the project expects to deepen understanding of these important processes, open up ways to make new antibiotics, and generate new knowledge about protein evolution. Intended outcomes include new biocatalysts based on the ancient ones, new antibiotic compounds active against resistant bacteria, and a richer understanding of how these proteins have evolved over the last 4 billion years. This promises significant benefits in the form of new ways to address the challenge posed by antimicrobial resistance to antibiotics, which is a serious threat to the continued effectiveness of current antibiotics.Read moreRead less
CRISPR-based pathway activation for bioactive molecule discovery in fungi. Fungi produce an incredible array of unique bioactive molecules, many of which have contributed greatly to humanity (e.g. the antibiotic penicillin, which has saved millions of lives since its discovery). DNA sequencing has revealed many fungi contain the genetic instructions to produce new molecules that have not been seen previously. However, these genes are “switched off" by default and cannot be accessed. This project ....CRISPR-based pathway activation for bioactive molecule discovery in fungi. Fungi produce an incredible array of unique bioactive molecules, many of which have contributed greatly to humanity (e.g. the antibiotic penicillin, which has saved millions of lives since its discovery). DNA sequencing has revealed many fungi contain the genetic instructions to produce new molecules that have not been seen previously. However, these genes are “switched off" by default and cannot be accessed. This project will develop innovative new methods to "hot-wire" these genes, allowing them to turn on and produce a treasure trove of new bioactive molecules. The outcomes of this project will transform our abilities to tap into the hidden potential of fungi to generate new lead molecules for the agricultural and medical industries.Read moreRead less
Micro-dissection of clathrins role in mitosis via chemical biology probes. This project aims to contribute to understanding the molecular mechanisms of the role of a key protein, clathrin, in cell division. In doing so it expects to reveal new approaches to stop uncontrolled cell division and proliferation, the hallmarks of cancer. The outcomes could in the long term inform breakthroughs in cancer treatment, significant enhancements in life quality and a reduction in cancer death rates.
Surface Chemistry meets Cell Biology: Molecular Level Control of Surface Architecture for Cell Adhesion and Migration. Biotechnological applications such as tissue engineering, bone supports, implantable materials, cell assays and biosensors all require detailed knowledge of how cells interact with their environment. The proposed research aims to provide this knowledge by developing unique modified surfaces to investigate white blood cell migration and adhesion. Additional expected outcome will ....Surface Chemistry meets Cell Biology: Molecular Level Control of Surface Architecture for Cell Adhesion and Migration. Biotechnological applications such as tissue engineering, bone supports, implantable materials, cell assays and biosensors all require detailed knowledge of how cells interact with their environment. The proposed research aims to provide this knowledge by developing unique modified surfaces to investigate white blood cell migration and adhesion. Additional expected outcome will contribute to our understanding of the many fundamental cellular processes such as cell growth, differentiation and cell death as well as the molecular basis of diseases such as inflammation, cancer, cardiovascular diseases and wound healing. This research program will establish Australia as a leading force in this new research field.Read moreRead less
Nanotherapeutics: nanoparticles with high specificity for the delivery and controlled release of drugs. This technology will deliver therapeutic drugs and/or MRI contrast agents to individual diseased cells with very high specificity and selectivity. The cells can be interogated to determine when they are "loaded" and the site of the "loaded" cells precisely determined. Drugs can be released photochemically. The administered dosage can be decreased with no loss of efficacy, and side effects re ....Nanotherapeutics: nanoparticles with high specificity for the delivery and controlled release of drugs. This technology will deliver therapeutic drugs and/or MRI contrast agents to individual diseased cells with very high specificity and selectivity. The cells can be interogated to determine when they are "loaded" and the site of the "loaded" cells precisely determined. Drugs can be released photochemically. The administered dosage can be decreased with no loss of efficacy, and side effects reduced. Read moreRead less
Biomagnification of the biotoxin BMAA in the environment. Using unique models and technics, the project aims to demonstrate that long-term exposure to the blue green algae toxin β-N-methylamino-l-alanine (BMAA) leads to uptake, accumulation and toxicity within the central nervous system. The risks for heath, mechanisms of contamination and toxicity of BMAA are very poorly understood. Algal blooms cost the Australian community more than $250 million each year and represent a major health issue fo ....Biomagnification of the biotoxin BMAA in the environment. Using unique models and technics, the project aims to demonstrate that long-term exposure to the blue green algae toxin β-N-methylamino-l-alanine (BMAA) leads to uptake, accumulation and toxicity within the central nervous system. The risks for heath, mechanisms of contamination and toxicity of BMAA are very poorly understood. Algal blooms cost the Australian community more than $250 million each year and represent a major health issue for human and fauna. This project aims to be the first to fully characterise BMAA mechanisms of contamination and neurotoxicity and to highlight the major environmental risk of exposure of human to BMAA. It also aims to develop new and unique detection and quantification tools for BMAA.Read moreRead less
Engineered Hydroxamic Acids for Zirconium-89 Positron Emission Tomography (PET) Imaging of Prostate Cancer. Positron emission tomography (PET) using a zirconium-89-ligand complex bound to a prostate-specific membrane antigen is used to detect and monitor prostate cancer. The hydroxamic acid-based ligand bound to zirconium has a high affinity towards iron, which can cause metal exchange in vivo and loss of radiotracer. The project will prepare new ligands with a higher specificity towards zirconi ....Engineered Hydroxamic Acids for Zirconium-89 Positron Emission Tomography (PET) Imaging of Prostate Cancer. Positron emission tomography (PET) using a zirconium-89-ligand complex bound to a prostate-specific membrane antigen is used to detect and monitor prostate cancer. The hydroxamic acid-based ligand bound to zirconium has a high affinity towards iron, which can cause metal exchange in vivo and loss of radiotracer. The project will prepare new ligands with a higher specificity towards zirconium over iron, and measure immuno-PET imaging activity. A second series of macrocyclic zirconium-specific ligands will be prepared to establish the relationship between variable water-lipid solubility and pharmacokinetic properties. The results will increase the capability of immuno-PET for prostate cancer detection and improve survival outcomes.Read moreRead less
Diene regenerative Diels-Alder reactions to access chemical scaffolds. This project aims to develop methods and strategies that allow rapid access to biologically active chemical scaffolds based on natural products. Natural products and their analogues are vital starting points for drug discovery as they provide unique chemical diversity. Without efficient methods for their production, it is not possible to exploit this diversity. This project will develop an efficient, modular strategy that wil ....Diene regenerative Diels-Alder reactions to access chemical scaffolds. This project aims to develop methods and strategies that allow rapid access to biologically active chemical scaffolds based on natural products. Natural products and their analogues are vital starting points for drug discovery as they provide unique chemical diversity. Without efficient methods for their production, it is not possible to exploit this diversity. This project will develop an efficient, modular strategy that will allow the preparation of a wide range of chemicals in a timely manner. Restoring access to potent biologically active materials is expected to generate chemical probes and lead to molecules that could have biomedical value.Read moreRead less
New metal-molecule binding motifs for self-assembled monolayers and nanodevices. The goal of this research is to investigate technologically interesting electronic materials using new molecular assemblies. We explore their application in some fundamental components of molecular electronic systems and anticipate that knowledge gained from our investigations will have significant impact on the field of nanotechnology, especially in the area of molecular electronics. Our basic research will contrib ....New metal-molecule binding motifs for self-assembled monolayers and nanodevices. The goal of this research is to investigate technologically interesting electronic materials using new molecular assemblies. We explore their application in some fundamental components of molecular electronic systems and anticipate that knowledge gained from our investigations will have significant impact on the field of nanotechnology, especially in the area of molecular electronics. Our basic research will contribute to Australia's reputation as a source of innovative research and ideas in an area where there is growing international momentum.Read moreRead less