Thioamide ligations: new technologies for peptide and protein synthesis. This project aims to develop novel amide-bond forming reactions for the chemical synthesis of peptides and proteins. New peptide ligation strategies, including an asparagine-based ligation and a residue-independent ligation will be developed that exploit the recent discovery of silver-promoted coupling reactions of thioamides. A novel late-stage, chemo-selective assembly of N-glycosylated asparagine residues in peptides and ....Thioamide ligations: new technologies for peptide and protein synthesis. This project aims to develop novel amide-bond forming reactions for the chemical synthesis of peptides and proteins. New peptide ligation strategies, including an asparagine-based ligation and a residue-independent ligation will be developed that exploit the recent discovery of silver-promoted coupling reactions of thioamides. A novel late-stage, chemo-selective assembly of N-glycosylated asparagine residues in peptides and proteins will also be developed. The outcomes of this research will lead to breakthroughs in synthetic methodologies for the assembly and functionalisation of peptides and proteins, thereby enabling access to a range of homogeneous, post translationally modified proteins though total chemical synthesis. These research outcomes will expand Australia's research capability and global competitiveness in the field of biotechnology, delivering significant benefits to the third largest manufacturing sector in Australia.Read moreRead less
Biosynthetic LEGO: enzymatic redesign to produce new vancomycin analogues. This project aims to uncover the reengineering potential of the biosynthetic machinery that produces glycopeptide antibiotics by advancing our understanding of how the core peptide production line functions. Natural product biosynthesis often produces complex peptide structures, with one important example being the glycopeptide antibiotics. This project expects to generate new knowledge about enzymatic peptide biosynthesi ....Biosynthetic LEGO: enzymatic redesign to produce new vancomycin analogues. This project aims to uncover the reengineering potential of the biosynthetic machinery that produces glycopeptide antibiotics by advancing our understanding of how the core peptide production line functions. Natural product biosynthesis often produces complex peptide structures, with one important example being the glycopeptide antibiotics. This project expects to generate new knowledge about enzymatic peptide biosynthesis using a highly interdisciplinary approach and previously developed tools. The anticipated outcomes of this project will be an enhanced understanding of how such complex peptide biosynthesis is performed, which is knowledge vital for future efforts to reengineer such biosynthetic peptide assembly lines as a series of modular LEGO blocks to produce new bioactive peptides.Read moreRead less
The mechanism of membrane disruption by antimicrobial peptides. Bacterial resistance to antibiotics is a growing crisis in modern medicine. Antibacterial peptides from Australian frogs represent a new class of potent and selective antibacterial agents. Understanding how these peptides kill bacteria but not vertebrate cells could lead to the design of new drugs for pharmaceutical and/or clinical purposes.
Development and application of new peptide ligation methods for the synthesis and structure-function studies of glycoproteins. Novel synthetic technologies will be developed in this project to facilitate the preparation of glycoproteins, which are of widespread biological and therapeutic interest. These methods will enable the preparation of pure glycoproteins for detailed biochemical and functional studies eventually leading to therapeutic and diagnostic applications.
Atomic details of antimicrobial peptides at work in live cells. This project aims to develop methods to determine the detailed structure of biologically important molecules in live cells to better understand how biomolecular structure is related to disease. The structure at the atomic level of the molecules of life is usually characterised by crystal or solution studies in model systems. However, the structure of many biologically important molecules depends on their environment. Using new instr ....Atomic details of antimicrobial peptides at work in live cells. This project aims to develop methods to determine the detailed structure of biologically important molecules in live cells to better understand how biomolecular structure is related to disease. The structure at the atomic level of the molecules of life is usually characterised by crystal or solution studies in model systems. However, the structure of many biologically important molecules depends on their environment. Using new instrumentation and labelling schemes, the project plans to use nuclear magnetic resonance methods to study antibiotics and antimicrobial peptides in live bacteria and human cells. The goal is to resolve how these molecules cross cell membranes and how biomolecular structure is related to activity, which may advance development in biotechnology and therapeutic treatments against drug-resistant infections.Read moreRead less
Understanding peptide bond formation in non-ribosomal peptide biosynthesis. This project aims to uncover the origins of selectivity exhibited by the biosynthetic machinery that produces non-ribosomal peptides through advancing our understanding of how the central peptide synthesis domain functions. This project intends to generate new knowledge about peptide biosynthesis using a highly interdisciplinary approach and essential tools that have been developed. The anticipated outcomes of this proje ....Understanding peptide bond formation in non-ribosomal peptide biosynthesis. This project aims to uncover the origins of selectivity exhibited by the biosynthetic machinery that produces non-ribosomal peptides through advancing our understanding of how the central peptide synthesis domain functions. This project intends to generate new knowledge about peptide biosynthesis using a highly interdisciplinary approach and essential tools that have been developed. The anticipated outcomes of this project will be an enhanced understanding of the structural basis for substrate selection exhibited during peptide synthesis, revealing the specificity code of these key domains. This knowledge is vital for future efforts to reengineer such biosynthetic peptide assembly lines to produce new bioactive peptides.Read moreRead less
Functional studies of tyrosine sulfation using synthetic sulfoproteins. This project aims to address a lack of knowledge about how post-translational sulfation of tyrosine residues influences protein function. The project will develop a synthetic platform for the rapid and efficient generation of libraries of site-selectively sulfated proteins. The new methods will be used to study bioactive sulfated proteins secreted by ticks that dampen the inflammatory response and prevent blood from clotting ....Functional studies of tyrosine sulfation using synthetic sulfoproteins. This project aims to address a lack of knowledge about how post-translational sulfation of tyrosine residues influences protein function. The project will develop a synthetic platform for the rapid and efficient generation of libraries of site-selectively sulfated proteins. The new methods will be used to study bioactive sulfated proteins secreted by ticks that dampen the inflammatory response and prevent blood from clotting. Underpinned by the ability to access synthetic sulfoproteins, expected outcomes include a detailed understanding of how tyrosine sulfation can modulate function and stability of antibodies and proteins with anticoagulant and anti-inflammatory activities. Significant benefits of the project will include breakthrough technologies for the preparation of homogeneously modified proteins, which will strengthen Australia’s growing biotechnology sector.Read moreRead less
Solid phase synthesis of side-chain cross-linked peptide oligomers. This research will provide a unique opportunity to investigate the biological pathways and causative factors leading to diseases such as Alzheimer’s disease. Such information will guide the design and development of therapeutic strategies and diagnostic reagents.
A new platform technology for gene therapy . The project aims to make a landmark contribution to biological science by enabling programmed delivery of therapeutic payloads from biocompatible materials. It will employ a novel synthetic biology approach to form two distinct peptide-enabled molecular architectures in a single system. This is expected to deliver a platform technology that will allow successful programmed delivery of viral vectors. The project is likely to deliver significant societa ....A new platform technology for gene therapy . The project aims to make a landmark contribution to biological science by enabling programmed delivery of therapeutic payloads from biocompatible materials. It will employ a novel synthetic biology approach to form two distinct peptide-enabled molecular architectures in a single system. This is expected to deliver a platform technology that will allow successful programmed delivery of viral vectors. The project is likely to deliver significant societal benefit as a fundamental scientific platform, improving Australia's capacity and impact in the agriculture and the healthcare sectors. The platform technology has the potential to increase the quality of life for patients and their carers, while also produce fitter, healthier livestock.Read moreRead less
Structure and activity determination of membrane-active peptides. Membrane-active peptides, such as antimicrobial and amyloid (Ab) peptides, play an important role in disease. With the growth of antibiotic resistance and increase in Alzheimer’s disease, which is epitomised by plaques of Ab, new drugs are required. Although Ab is toxic in neuronal cell cultures and disrupts cell membranes, the mechanism is unknown. Antimicrobial peptides that target bacterial membranes have evolved as a defence m ....Structure and activity determination of membrane-active peptides. Membrane-active peptides, such as antimicrobial and amyloid (Ab) peptides, play an important role in disease. With the growth of antibiotic resistance and increase in Alzheimer’s disease, which is epitomised by plaques of Ab, new drugs are required. Although Ab is toxic in neuronal cell cultures and disrupts cell membranes, the mechanism is unknown. Antimicrobial peptides that target bacterial membranes have evolved as a defence mechanism against infection and, since membranes show little genetic adaptation, could be drug candidates. Model membranes will be developed to elucidate the mechanism of action and key molecular features that determine affinity for membrane lipids of an antimicrobial peptide and full length Ab peptides.Read moreRead less