Force Fields for Structure Refinement and Computational Drug Design. The ability to model molecular systems at an atomic level, as used in protein structure refinement or computational drug design, is critically dependent on the accuracy with which inter-atomic interactions are represented. Highly optimised and well-validated interaction parameters are available for common biomolecules, such as amino acids, sugars and lipids, but not for co-factors, substrates and potential drug molecules, or ot ....Force Fields for Structure Refinement and Computational Drug Design. The ability to model molecular systems at an atomic level, as used in protein structure refinement or computational drug design, is critically dependent on the accuracy with which inter-atomic interactions are represented. Highly optimised and well-validated interaction parameters are available for common biomolecules, such as amino acids, sugars and lipids, but not for co-factors, substrates and potential drug molecules, or other molecules of interest such as polymers and dendrimers. The aim of this project is to develop and validate geometric and interaction parameters (force fields) for complex organic molecules and use these to facilitate bio-molecular structure refinement and computational drug design.Read moreRead less
Improving empirical force fields: a big-data approach. This project aims to improve the ability to represent the thermodynamic properties of molecules of biological, pharmaceutical or materials interest by developing force fields capable of describing a diverse range of molecules both consistently and with high fidelity. The project aims to exploit a rapidly expanding, in-house database of parameterized molecular structures to develop highly optimised, well-validated parameters that are both con ....Improving empirical force fields: a big-data approach. This project aims to improve the ability to represent the thermodynamic properties of molecules of biological, pharmaceutical or materials interest by developing force fields capable of describing a diverse range of molecules both consistently and with high fidelity. The project aims to exploit a rapidly expanding, in-house database of parameterized molecular structures to develop highly optimised, well-validated parameters that are both consistent and transferable, enabling molecules of any size or complexity to be parameterised with a fidelity currently only possible for simple organics. This will provide significant benefits, such as helping to improve the accuracy and reliability of ligand: protein complexes determined experimentally, a limiting factor in computational drug design.Read moreRead less
Bioactive Peptides as Pharmacological Tools and Novel Drug Leads. Bioactive peptides are produced by all organisms and play numerous critical physiological roles, including in cellular communication, host defence and capture of prey. Peptides have huge potential as tools for studying roles of signalling pathways and as novel drugs due to their high affinity and selectivity for various therapeutically relevant targets. However their use has been limited by poor in vivo stability. This project is ....Bioactive Peptides as Pharmacological Tools and Novel Drug Leads. Bioactive peptides are produced by all organisms and play numerous critical physiological roles, including in cellular communication, host defence and capture of prey. Peptides have huge potential as tools for studying roles of signalling pathways and as novel drugs due to their high affinity and selectivity for various therapeutically relevant targets. However their use has been limited by poor in vivo stability. This project is focused on studying structural features of a range of peptides and their contributions to both activity and to resistance against degradation, with the aim to develop stabilised bioactive peptide sequences for in vivo applications, allowing the full potential of peptides as drugs to be realised.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.
A new source of bivalent molecules from nature. This project aims to describe a new class of naturally occurring multivalent molecules termed secreted cysteine-rich repeat proteins (SCREPs). Multivalency is a key feature of molecular interaction in biology, underlying the high specificity and potency found in many proteins. Focusing on bivalent peptides, the project will generate a database of bioactive SCREPs with similarity to known bioactive peptides, and develop new recombinant methods for t ....A new source of bivalent molecules from nature. This project aims to describe a new class of naturally occurring multivalent molecules termed secreted cysteine-rich repeat proteins (SCREPs). Multivalency is a key feature of molecular interaction in biology, underlying the high specificity and potency found in many proteins. Focusing on bivalent peptides, the project will generate a database of bioactive SCREPs with similarity to known bioactive peptides, and develop new recombinant methods for their production. The project will use advanced nuclear magnetic resonance spectroscopy to characterise members of this new class, providing new insights into the design of bivalent and multivalent peptides and establishing a new source of molecules with applications in the rapidly growing biotechnology sector.Read moreRead less
Making peptides orally bioavailable. Bioactive peptides are exceptionally useful molecules, however to fully realise their exciting applications key limitations need to be overcome: they can't be delivered orally and they do not last long in the body. This project aims to develop a molecular tag that can dramatically enhance both the oral absorption and time in the body of a peptide. This will include identifying the key elements of the tag required for function, the breadth of peptide cargoes i ....Making peptides orally bioavailable. Bioactive peptides are exceptionally useful molecules, however to fully realise their exciting applications key limitations need to be overcome: they can't be delivered orally and they do not last long in the body. This project aims to develop a molecular tag that can dramatically enhance both the oral absorption and time in the body of a peptide. This will include identifying the key elements of the tag required for function, the breadth of peptide cargoes it can be applied to and the mechanisms underlying this technology. The outcomes of this project will facilitate the future development of peptides for biotechnology, pharmaceutical and veterinary applications.Read moreRead less
Exploring the novel structural features of influenza virus sialidase. The outcomes of this project will provide a deeper mechanistic understanding of influenza virus sialidase and the importance of the enzyme's flexible loops in carbohydrate recognition. Specifically, this project will improve our understanding of fundamental aspects of inhibitor binding by influenza virus sialidases.
Australian Laureate Fellowships - Grant ID: FL150100146
Funder
Australian Research Council
Funding Amount
$2,977,310.00
Summary
Taking Australia from the farm to the pharm. Taking Australian from the farm to the pharm: This fellowship project aims to design novel drugs based on cyclic peptides that will be expressed in the seeds of plants to produce bio-pills — saving money for patients and the health care system. Plants produce unique cyclic peptides (mini-proteins) to protect themselves from pests and pathogens. This project aims to chemically redesign these peptides to produce stable protein-based pharmaceuticals that ....Taking Australia from the farm to the pharm. Taking Australian from the farm to the pharm: This fellowship project aims to design novel drugs based on cyclic peptides that will be expressed in the seeds of plants to produce bio-pills — saving money for patients and the health care system. Plants produce unique cyclic peptides (mini-proteins) to protect themselves from pests and pathogens. This project aims to chemically redesign these peptides to produce stable protein-based pharmaceuticals that can be eaten. It is hoped that these designer pharmaceuticals will be inexpensive, effective, easy to ingest and without the side effects of traditional drugs. The outcomes of this project are anticipated to be high-value drugs and agri-chemicals which will open up new high-value crops for Australian farmers and a new Australian ‘pharming’ industry.Read moreRead less
The chemistry and biology of circular proteins. This project aims to develop plant-derived ultra-stable cyclic peptides for pharmaceutical and agricultural applications. The project will use innovative new methodologies for discovery, chemical synthesis and engineering of these molecules. It is expected that the project will contribute to high value biotechnology and agricultural industries in Australia. The proposed outcomes will include fundamental new knowledge on the biosynthesis of circular ....The chemistry and biology of circular proteins. This project aims to develop plant-derived ultra-stable cyclic peptides for pharmaceutical and agricultural applications. The project will use innovative new methodologies for discovery, chemical synthesis and engineering of these molecules. It is expected that the project will contribute to high value biotechnology and agricultural industries in Australia. The proposed outcomes will include fundamental new knowledge on the biosynthesis of circular proteins in plants, new approaches for their discovery and technologies for applying them as drug leads and agricultural products.Read moreRead less
Natural product scaffolds: an approach to privileged structures. Based on the fact that nature has provided approximately 50 per cent of current drugs, the purpose of this project is to identify scaffolds that are critical for the biological interactions. The expected outcome is to build libraries based on the scaffolds and identify new privileged structures for application in drug discovery.