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Chemical synthesis of cancer-associated glycoproteins. Glycosylation of proteins is an extremely common event which plays an important role in a variety of biological processes. Aberrant glycosylation and over-production of glycoproteins is associated with numerous cancer types (including breast, prostate, ovarian and small lung) and are recognised as promising agents for disease diagnosis and vaccine development. A range of cancer-associated glycoproteins will be synthesised in this research p ....Chemical synthesis of cancer-associated glycoproteins. Glycosylation of proteins is an extremely common event which plays an important role in a variety of biological processes. Aberrant glycosylation and over-production of glycoproteins is associated with numerous cancer types (including breast, prostate, ovarian and small lung) and are recognised as promising agents for disease diagnosis and vaccine development. A range of cancer-associated glycoproteins will be synthesised in this research program using a number of novel chemical technologies. These glycoproteins will be used to develop cancer vaccines and diagnostics. Cancer is a severe burden on the Australian community and on the economy, therefore this research will be of significant benefit to Australia.Read moreRead less
Chemical tools for the study of mycobacterial glycolipid biosynthesis. Mycobacteria are responsible for human morbidity and mortality on a immense scale. The cell wall structure of these bacteria is extremely complex and offers many novel therapeutic opportunities. In this proposal we will use a synergetic interplay of chemistry, biochemistry and microbiology to study the biosynthesis of essential cell wall molecules conserved across all mycobacteria, the phosphatidylinositol mannosides. Substr ....Chemical tools for the study of mycobacterial glycolipid biosynthesis. Mycobacteria are responsible for human morbidity and mortality on a immense scale. The cell wall structure of these bacteria is extremely complex and offers many novel therapeutic opportunities. In this proposal we will use a synergetic interplay of chemistry, biochemistry and microbiology to study the biosynthesis of essential cell wall molecules conserved across all mycobacteria, the phosphatidylinositol mannosides. Substrates and inhibitors will be prepared and studied using novel biochemical and microbiological methods. This project will enhance our understanding of cell wall synthesis in mycobacteria and will lay the ground work for the discovery of novel antibiotics.Read moreRead less
Nanotechnology-Enhanced Vaccines: New inulin bioconjugates to defeat global pandemic threats. Inulin-based adjuvants have the potential to revolutionise the vaccine arena; man's critical first line of defence against infectious disease. Any breakthrough in developing completely safe new adjuvants, will therefore be of major global significance, and will play a vital role in the maintenance of global health for decades. New and completely safe vaccine adjuvants are a vital step in the developmen ....Nanotechnology-Enhanced Vaccines: New inulin bioconjugates to defeat global pandemic threats. Inulin-based adjuvants have the potential to revolutionise the vaccine arena; man's critical first line of defence against infectious disease. Any breakthrough in developing completely safe new adjuvants, will therefore be of major global significance, and will play a vital role in the maintenance of global health for decades. New and completely safe vaccine adjuvants are a vital step in the development of improved vaccine technology in the 21st century. This project addresses two National Research Priorities, Namely Promoting and Maintaining Good Health and Safeguarding Australia. On commercialization, this will then be an important Australian contribution towards protecting the nation against any future pandemic outbreaks.Read moreRead less
Studies on the stereospecific interaction between aldose reductase and inhibitor. There is no therapy specific for treatment of diabetes complications accepted worldwide. The enzyme aldose reductase has shown promising results as a drug target for preventing or delaying the onset of the complications. The structures of human aldose reductase holoenzyme in complex with stereoisomers of the potent inhibitor Fidarestat will be determined at high resolution in order to elucidate the binding modes re ....Studies on the stereospecific interaction between aldose reductase and inhibitor. There is no therapy specific for treatment of diabetes complications accepted worldwide. The enzyme aldose reductase has shown promising results as a drug target for preventing or delaying the onset of the complications. The structures of human aldose reductase holoenzyme in complex with stereoisomers of the potent inhibitor Fidarestat will be determined at high resolution in order to elucidate the binding modes responsible for the differences in their inhibitory potencies. The results may lead to the design of better inhibitors of the enzyme for the treatment of diabetes sufferers, at least until better methods for maintaining metabolic control are developed.Read moreRead less
Structure-based discovery of dipeptidyl peptidase IV inhibitors. Diabetes afflicts approximately 151 million people worldwide, with an estimated increase to 221 million by 2010. To date, no therapy for the treatment of diabetes complications is widely accepted. The enzyme dipeptidyl peptidase IV has shown promising results as a target for the treatment of type 2 diabetes. Structural studies of dipeptidyl peptidase IV in complex with inhibitor will be conducted to elucidate the details of the e ....Structure-based discovery of dipeptidyl peptidase IV inhibitors. Diabetes afflicts approximately 151 million people worldwide, with an estimated increase to 221 million by 2010. To date, no therapy for the treatment of diabetes complications is widely accepted. The enzyme dipeptidyl peptidase IV has shown promising results as a target for the treatment of type 2 diabetes. Structural studies of dipeptidyl peptidase IV in complex with inhibitor will be conducted to elucidate the details of the enzyme-inhibitor interaction. The results will be used to identify the molecular basis of potency and selectivity of dipeptidyl peptidase IV inhibitors and may lead to the discovery of pharmaceutical agents for the treatment of diabetes sufferers.Read moreRead less
Crystallographic studies of aldose and aldehyde reductases. The ability of aldose reductase to reduce the excess glucose that results from the hyperglycaemia of diabetes has been linked to the development of diabetic complications. Recent studies link the lack of a clinically suitable aldose reductase inhibitor to lack of inhibitor selectivity. The structures of the complexes of aldose and aldehyde reductases with various inhibitors should allow us to establish the important aspects of the inh ....Crystallographic studies of aldose and aldehyde reductases. The ability of aldose reductase to reduce the excess glucose that results from the hyperglycaemia of diabetes has been linked to the development of diabetic complications. Recent studies link the lack of a clinically suitable aldose reductase inhibitor to lack of inhibitor selectivity. The structures of the complexes of aldose and aldehyde reductases with various inhibitors should allow us to establish the important aspects of the inhibitor interaction with the residues of the active site. This information will be used in the design of more specific aldose reductase inhibitors.Read moreRead less
Dissociation of a Tetrameric Enzyme with Interface-Targeted Peptides. With antibiotic resistance on the rise, there is an urgent need to develop new antibiotics and an equally urgent need to characterise new antibiotic targets. One such target is dihydrodipicolinate synthase (DHDPS) which catalyses the critical step in lysine and cell wall biosynthesis in bacteria. This proposal aims to generate new drugs targeting DHDPS for effective and rapid treatment of bacterial infections, including gastro ....Dissociation of a Tetrameric Enzyme with Interface-Targeted Peptides. With antibiotic resistance on the rise, there is an urgent need to develop new antibiotics and an equally urgent need to characterise new antibiotic targets. One such target is dihydrodipicolinate synthase (DHDPS) which catalyses the critical step in lysine and cell wall biosynthesis in bacteria. This proposal aims to generate new drugs targeting DHDPS for effective and rapid treatment of bacterial infections, including gastroenteritis. Recent statistics show that over 5 million Australians suffer from gastroenteritis each year and hospitalisation for this infection is nearly seven times higher for indigenous than non-indigenous children. Accordingly, this research has the potential to assure a healthier future for millions of Australians.Read moreRead less
Synthesis of new heterocyclic analogues of isoflavones. Intake of high dietary isoflavonoid phytoestrogens has been linked to low prevalence of hormone-dependent cancers such as breast and prostate cancer, and heart disease. The isoflavones resemble endogenous estradiol in structure, and have been shown to display weak estrogenic activity. Novogen Limited is pioneering the development of novel drug candidates based on isoflavones. This collaborative research project deals with the development o ....Synthesis of new heterocyclic analogues of isoflavones. Intake of high dietary isoflavonoid phytoestrogens has been linked to low prevalence of hormone-dependent cancers such as breast and prostate cancer, and heart disease. The isoflavones resemble endogenous estradiol in structure, and have been shown to display weak estrogenic activity. Novogen Limited is pioneering the development of novel drug candidates based on isoflavones. This collaborative research project deals with the development of synthetic methodologies for the preparation of new analogues of isoflavone metabolites as potential drug candidates. The target compounds will be evaluated for possible therapeutic use by the industry partner.Read moreRead less
Synthesis of pyrroloquinoline analogues of isoflavone metabolites. Cancer and heart disease are the two main diseases that affect our society indiscriminately and put enormous drains on healthcare resources. The intake of high dietary isoflavonoid phytoestrogens has been linked to low prevalence of cancers and heart disease. Novogen Limited is pioneering the development of novel drug candidates based on phytoestrogen metabolites. This collaborative research project deals with the development ....Synthesis of pyrroloquinoline analogues of isoflavone metabolites. Cancer and heart disease are the two main diseases that affect our society indiscriminately and put enormous drains on healthcare resources. The intake of high dietary isoflavonoid phytoestrogens has been linked to low prevalence of cancers and heart disease. Novogen Limited is pioneering the development of novel drug candidates based on phytoestrogen metabolites. This collaborative research project deals with the development of synthetic methodologies for the preparation of new analogues of phytoestrogen metabolites as potential drug candidates. The target compounds will be evaluated for possible therapeutic use by the industry partner.Read moreRead less
Inhibitors of meso-diaminopimelic acid (meso-DAP) and lysine biosynthesis: targeting dihydrodipicolinate synthase. With antibiotic resistance on the rise, there is an urgent need to develop new antibiotics with novel modes of action. This project aims to generate new drug candidates that target dihydrodipicolinate synthase (DHDPS) - the first enzyme in the synthesis of the bacterial cell wall - using a triple-pronged approach. This novel approach will allow for the development of new drugs to tr ....Inhibitors of meso-diaminopimelic acid (meso-DAP) and lysine biosynthesis: targeting dihydrodipicolinate synthase. With antibiotic resistance on the rise, there is an urgent need to develop new antibiotics with novel modes of action. This project aims to generate new drug candidates that target dihydrodipicolinate synthase (DHDPS) - the first enzyme in the synthesis of the bacterial cell wall - using a triple-pronged approach. This novel approach will allow for the development of new drugs to treat a range of pathogenic bacteria, including "Golden Staph".Read moreRead less