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Enhanced drug delivery using nanoparticulate dendrimer vectors. Many drug candidates fail during development because of low and variable absorption after oral administration. This project seeks to investigate the utility of specialised nanometer-sized macromolecules (dendrimers), to facilitate the improved delivery of drug molecules where low aqueous solubility is the principle limitation to drug absorption and will also be explored as vectors to specifically target drugs to intestinal lymphoid ....Enhanced drug delivery using nanoparticulate dendrimer vectors. Many drug candidates fail during development because of low and variable absorption after oral administration. This project seeks to investigate the utility of specialised nanometer-sized macromolecules (dendrimers), to facilitate the improved delivery of drug molecules where low aqueous solubility is the principle limitation to drug absorption and will also be explored as vectors to specifically target drugs to intestinal lymphoid (immune) tissue. This project will link the drug delivery expertise of Monash University with the experience in dendrimer design of the Australian biotechnology company Starpharma to provide concrete delivery solutions for the rapidly expanding biotechnology industry in Australia.Read moreRead less
Rational Design of Pegylated Dendrimer Nanostructures for Site Specific Drug Delivery. This project will provide technological advances with significant benefits in terms of improved drug treatment, and therefore health outcomes for Australia. The project builds on areas of research strength in Australia (nanotechnology and biotechnology/biomaterials) and will add considerably to the expanding Australian expertise-base in dendrimer technology (in which it is a world leader). The interdisciplinar ....Rational Design of Pegylated Dendrimer Nanostructures for Site Specific Drug Delivery. This project will provide technological advances with significant benefits in terms of improved drug treatment, and therefore health outcomes for Australia. The project builds on areas of research strength in Australia (nanotechnology and biotechnology/biomaterials) and will add considerably to the expanding Australian expertise-base in dendrimer technology (in which it is a world leader). The interdisciplinary nature of this project will also result in a unique training program for the researchers included in this grant. Such experience is in great demand, particularly in Australia where the burgeoning start-up discovery industry is critically short of personnel with skills in drug delivery.Read moreRead less
Synthetic derivatives of capsaicin and gingerols as analgesics acting at the vanilloid receptor. This project aims to prepare alpha-hydroxyketones and gingerol derivatives acting at vanilloid (VR1) receptor with potential analgesic activity. These compounds will be tested for their ability to activate the VR1 receptor, desensitize the receptor and release neuropeptides associated with pain pathways. The development of these novel compounds will contribute towards understanding the mechanisms of ....Synthetic derivatives of capsaicin and gingerols as analgesics acting at the vanilloid receptor. This project aims to prepare alpha-hydroxyketones and gingerol derivatives acting at vanilloid (VR1) receptor with potential analgesic activity. These compounds will be tested for their ability to activate the VR1 receptor, desensitize the receptor and release neuropeptides associated with pain pathways. The development of these novel compounds will contribute towards understanding the mechanisms of VR1 receptor activation and provide information on how the VR1 receptor is regulated. We will determine and compare neurotoxicity of these compounds to capsaicin which is known to possess neurotoxic activity. The outcome of this project may result in effective agents for better pain management.
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Therapeutic approaches to treat human immunodeficiency virus infection: development of HIV-1 integrase inhibitors. This project aims to assist the development of new anti-HIV drugs, which would benefit the 15000 Australians and over 40 million people worldwide who are currently infected with this terrible disease. The project will utilise state of the art technologies - including the Australian Synchrotron when it is commissioned in 2007 - to identify and synthesise compounds as new leads for th ....Therapeutic approaches to treat human immunodeficiency virus infection: development of HIV-1 integrase inhibitors. This project aims to assist the development of new anti-HIV drugs, which would benefit the 15000 Australians and over 40 million people worldwide who are currently infected with this terrible disease. The project will utilise state of the art technologies - including the Australian Synchrotron when it is commissioned in 2007 - to identify and synthesise compounds as new leads for the treatment of HIV.Read moreRead less
Targeting virulence of Pseudomonas aeruginosa by inhibiting oxidative protein folding. Our research will lead to the development of compounds with a novel anti-virulence/antibacterial mode of action for further drug development.
Mechanisms of enhancement of absorption of poorly water-soluble drugs from the gastrointestinal tract mediated by lipids, surfactants and polymers. This project will provide technological advances with significant benefits in terms of improved drug treatment, and therefore health outcomes for Australia. The projects builds on internationally recognised research strengths at Monash University in lipid-based drug delivery, and connects Monash and Australia with applied research in the multination ....Mechanisms of enhancement of absorption of poorly water-soluble drugs from the gastrointestinal tract mediated by lipids, surfactants and polymers. This project will provide technological advances with significant benefits in terms of improved drug treatment, and therefore health outcomes for Australia. The projects builds on internationally recognised research strengths at Monash University in lipid-based drug delivery, and connects Monash and Australia with applied research in the multinational pharmaceutical industry. This will enhance the standing of Australian biomedical research in the pharmaceutical world and directly facilitate a partnership between Monash and Capsugel in commercialisation of the outcomes of the project. The project will also train Australian scientists in skills that are in great demand in the developing pharmaceutical industry in Australia.Read moreRead less
DsbA: A target for the design of drug candidates as selective inhibitors of oxidative protein folding in Gram negative bacteria. There is a clear need for development of novel antibiotics which are capable of treating the increasingly prevalent strains of pathogenic bacteria that are resistant to currently available drugs. In this proposal we will design novel inhibitors of bacterial enzymes that are required for the correct folding of a variety of proteins and test the effects of these molecule ....DsbA: A target for the design of drug candidates as selective inhibitors of oxidative protein folding in Gram negative bacteria. There is a clear need for development of novel antibiotics which are capable of treating the increasingly prevalent strains of pathogenic bacteria that are resistant to currently available drugs. In this proposal we will design novel inhibitors of bacterial enzymes that are required for the correct folding of a variety of proteins and test the effects of these molecules on enzyme activity, bacterial growth and antibiotic resistance. Specific inhibitors of these enzymes constitute a novel strategy for the treatment of bacteria that have developed resistance to existing antimicrobial drugs.
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BIOCATALYSTS MINED FROM CYTOCHROME P450 LIBRARIES: AN INNOVATIVE TOOL FOR ACCELERATING DRUG DEVELOPMENT. The cytochrome P450s (P450s) are a family of enzymes that are perhaps the most versatile biological catalysts known. DNA shuffling is an emerging technique that takes the genes encoding families of enzymes and creates libraries of catalysts with both improved and novel properties. We will obtain proof of concept that shuffled P450 libraries can be screened and optimized for use as biocatalys ....BIOCATALYSTS MINED FROM CYTOCHROME P450 LIBRARIES: AN INNOVATIVE TOOL FOR ACCELERATING DRUG DEVELOPMENT. The cytochrome P450s (P450s) are a family of enzymes that are perhaps the most versatile biological catalysts known. DNA shuffling is an emerging technique that takes the genes encoding families of enzymes and creates libraries of catalysts with both improved and novel properties. We will obtain proof of concept that shuffled P450 libraries can be screened and optimized for use as biocatalysts in drug development. The methodologies developed here will overcome two critical bottlenecks in current drug development: the optimisation and metabolic profiling of new drug candidates. This will yield important benefits in accelerating the optimisation and safety testing of drugs under development.Read moreRead less
Drug binding to human fatty acid binding proteins: a mechanism of cellular transport for poorly water soluble drugs. Considerable recent effort has been directed towards the development of Australia as a focal point for biotechnology and drug discovery. The principle operational focus of this effort has been the identification of potent and active new chemical entities. In order for these new molecules to be most useful in the community, however, they must be active after oral administration. Th ....Drug binding to human fatty acid binding proteins: a mechanism of cellular transport for poorly water soluble drugs. Considerable recent effort has been directed towards the development of Australia as a focal point for biotechnology and drug discovery. The principle operational focus of this effort has been the identification of potent and active new chemical entities. In order for these new molecules to be most useful in the community, however, they must be active after oral administration. This project will examine the fundamental mechanisms by which drugs are absorbed across the cells lining the intestine and will provide insight critical to the design and development of new drugs that are both potent and orally active. Read moreRead less
The role of fatty acid binding proteins in the binding and transport of lipophilic drugs. Poorly water-soluble drugs must cross the aqueous cytoplasm of intestinal cells if they are to be absorbed following oral administration. The mechanisms by which this occurs are currently unknown. We have shown that some lipophilic drugs are capable of binding to cytosolic transport proteins called fatty acid binding proteins (FABPs). We propose to use a range of physical techniques including NMR spectrosco ....The role of fatty acid binding proteins in the binding and transport of lipophilic drugs. Poorly water-soluble drugs must cross the aqueous cytoplasm of intestinal cells if they are to be absorbed following oral administration. The mechanisms by which this occurs are currently unknown. We have shown that some lipophilic drugs are capable of binding to cytosolic transport proteins called fatty acid binding proteins (FABPs). We propose to use a range of physical techniques including NMR spectroscopy, calorimetry and fluorescence firstly to identify the nature of drug binding to FABP and secondly to determine the effect of binding on drug transport.Read moreRead less