Novel target of amiloride analogues - picornaviral RNA polymerase. Picornaviruses cause a range of diseases such as poliomyelitis, meningitis, myocarditis, hepatitis A, neonatal sepsis and common cold. No antiviral treatment is available for these infections. Nearly 50% of antiviral drugs used in medicine are viral polymerase inhibitors; however picornaviral RNA polymerase has been largely overlooked as a drug target. We have discovered a group of compounds that inhibit picornaviral RNA polymera ....Novel target of amiloride analogues - picornaviral RNA polymerase. Picornaviruses cause a range of diseases such as poliomyelitis, meningitis, myocarditis, hepatitis A, neonatal sepsis and common cold. No antiviral treatment is available for these infections. Nearly 50% of antiviral drugs used in medicine are viral polymerase inhibitors; however picornaviral RNA polymerase has been largely overlooked as a drug target. We have discovered a group of compounds that inhibit picornaviral RNA polymerase. This project aims to define the inhibition mechanism and to evaluate a potential use of these compounds for antiviral drug development.Read moreRead less
Total Synthesis of the Microsclerodermins: Anti-fungal Cyclic Peptides. Fungal infections are one of the major causes of morbidity and mortality in the increasing immunocompromised patient population, which includes AIDS, chemotherapy and organ transplant patients. The aim of this project is to discover new anti-fungal treatments for drug-resistant pathogenic fungal infections, based on the microsclerodermin family of natural products. The small quantity of microsclerodermin isolated from the na ....Total Synthesis of the Microsclerodermins: Anti-fungal Cyclic Peptides. Fungal infections are one of the major causes of morbidity and mortality in the increasing immunocompromised patient population, which includes AIDS, chemotherapy and organ transplant patients. The aim of this project is to discover new anti-fungal treatments for drug-resistant pathogenic fungal infections, based on the microsclerodermin family of natural products. The small quantity of microsclerodermin isolated from the natural environment hampers the development of anti-fungal agents from this natural product. Innovative synthetic methods will be developed to prepare large quantities of microsclerodermins and related compounds for biological testing, thereby furthering the development of this promising class of anti-fungal drugs.Read moreRead less
Design and Development of HIV-1 Integrase Inhibitors Based on a Natural Product Lead. HIV/AIDS is a significant health problem with over 40 million people infected with HIV worldwide. Resistance to current drugs is rising rapidly and new therapeutics are urgently needed. This project will bring together local expertise in organic synthesis and virology in order to develop new and better treatments for HIV/AIDS. Ultimately, Australians with HIV may benefit directly from anti-HIV compounds produce ....Design and Development of HIV-1 Integrase Inhibitors Based on a Natural Product Lead. HIV/AIDS is a significant health problem with over 40 million people infected with HIV worldwide. Resistance to current drugs is rising rapidly and new therapeutics are urgently needed. This project will bring together local expertise in organic synthesis and virology in order to develop new and better treatments for HIV/AIDS. Ultimately, Australians with HIV may benefit directly from anti-HIV compounds produced and may also benefit from advances in our understanding of this elusive virus resulting from the project.Read moreRead less
Raman and synchrotron spectroscopy of nano-scale drug interactions and molecular processes in single living cells. The need for potent low-cost drugs is ever increasing, yet effective ways to screen for new drugs remain elusive. A spectroscopic approach to screening drugs in living cells would seem a logical alternative to chemically based and morphological methods that are the status quo. In this context we are developing methodology to analyse molecular target sites in single living cells for ....Raman and synchrotron spectroscopy of nano-scale drug interactions and molecular processes in single living cells. The need for potent low-cost drugs is ever increasing, yet effective ways to screen for new drugs remain elusive. A spectroscopic approach to screening drugs in living cells would seem a logical alternative to chemically based and morphological methods that are the status quo. In this context we are developing methodology to analyse molecular target sites in single living cells for two of the most devastating diseases to afflict human kind, namely malaria and cancer. New ways of rapidly screening drugs in living cells prior to clinical trials will save an enormous amount of time, money and ultimately lives.Read moreRead less
Synthetic Molybdenum Enzymes. This project aims to produce synthetic molybdenum (Mo) enzymes, small molecules that share structural and functional attributes with the crucially important molybdopterin?Mo enzymes. These ubiquitous enzymes are essential for plant and animal health, natural cycles involving carbon, nitrogen and sulfur, and global climate control and atmospheric albedo (reflectance); consequently, they impact heavily on commerce, the environment and society. The study will provid ....Synthetic Molybdenum Enzymes. This project aims to produce synthetic molybdenum (Mo) enzymes, small molecules that share structural and functional attributes with the crucially important molybdopterin?Mo enzymes. These ubiquitous enzymes are essential for plant and animal health, natural cycles involving carbon, nitrogen and sulfur, and global climate control and atmospheric albedo (reflectance); consequently, they impact heavily on commerce, the environment and society. The study will provide urgently needed insights into the fundamental Mo?sulfur chemistry of the enzyme active sites and inform efforts to reduce the negative impacts of enzyme dysfunction and the design of new commercial catalysts.Read moreRead less
Bioinorganic Chemistry of Molybdenum. Enzymes containing the trace element molybdenum play crucial roles in plant, animal and human health, drug metabolism, environmental processes and climate. This international, multidisciplinary project will advance our understanding of the structure and function of these enzymes at the atomic level and inform strategies to reduce the impact of crop, livestock and human diseases and adverse environmental (e.g. algal blooms, leaching of toxic arsenic) and clim ....Bioinorganic Chemistry of Molybdenum. Enzymes containing the trace element molybdenum play crucial roles in plant, animal and human health, drug metabolism, environmental processes and climate. This international, multidisciplinary project will advance our understanding of the structure and function of these enzymes at the atomic level and inform strategies to reduce the impact of crop, livestock and human diseases and adverse environmental (e.g. algal blooms, leaching of toxic arsenic) and climatic events. Effective strategies would be of enormous social and economic benefit to Australia. The training of skilled scientists and access to major overseas facilities are additional benefits of the project.Read moreRead less
Structural determination of respiratory membrane protein complexes by X-ray crystallography. Membrane proteins form only 0.3% of the available protein structures in the protein data bank (PDB), yet 30% of the proteins in the human genome and 50% of human drug targets are membrane proteins. We have managed to increase the success rate through rational screening and development of new crystallization screens, with downstream implications for basic and medical research. Results from this proposal w ....Structural determination of respiratory membrane protein complexes by X-ray crystallography. Membrane proteins form only 0.3% of the available protein structures in the protein data bank (PDB), yet 30% of the proteins in the human genome and 50% of human drug targets are membrane proteins. We have managed to increase the success rate through rational screening and development of new crystallization screens, with downstream implications for basic and medical research. Results from this proposal will receive international recognition and will encourage more research in this field, attracting international funding, and create new research opportunities. Read moreRead less
The Design and Synthesis of Inhibitors of Human Immunodeficiency (HIV) Budding. We have a very exciting and revolutionary approach to drug design by exploiting the exquisite potent action of peptides and at the same time overcome their shortcomings as drug candidates in that they are rapidly degraded in the body. We do this by slightly modifying their chemical structure but at the same time maintaining their biological activity. We will apply this new approach to a novel protein target to inhibi ....The Design and Synthesis of Inhibitors of Human Immunodeficiency (HIV) Budding. We have a very exciting and revolutionary approach to drug design by exploiting the exquisite potent action of peptides and at the same time overcome their shortcomings as drug candidates in that they are rapidly degraded in the body. We do this by slightly modifying their chemical structure but at the same time maintaining their biological activity. We will apply this new approach to a novel protein target to inhibit one of the main steps in the budding of Human Immunodeficiency (HIV) from infected cells. This unique combination of novel chemistry and drug design target makes this project highly innovative and with enormous potential to accelerate the identification of new drugs for HIV treatment.Read moreRead less
Free Radicals in Chemistry and Biology: A Computational Quantum Chemistry Investigation. This proposal aims to carry out state-of-the-art chemistry research using computers rather than traditional laboratory techniques. Free radicals, which have widespread importance in the multibillion dollar polymer and health industries, form the centrepiece of the proposal. These are highly reactive substances that are difficult to study by conventional experimental techniques but ideal to study using compu ....Free Radicals in Chemistry and Biology: A Computational Quantum Chemistry Investigation. This proposal aims to carry out state-of-the-art chemistry research using computers rather than traditional laboratory techniques. Free radicals, which have widespread importance in the multibillion dollar polymer and health industries, form the centrepiece of the proposal. These are highly reactive substances that are difficult to study by conventional experimental techniques but ideal to study using computers. The increased understanding of free radicals that will stem from this research may help in dealing with ageing, and afflictions such as hardening of the arteries and vitamin B12 deficiency. It will also result in the training at the highest level of new generations of chemists in this exciting field of "chemistry with computers".Read moreRead less
Computational Quantum Chemistry Study of Molecular Structures, Stabilities and Reactions. Computational quantum chemistry is revolutionizing the study and practice of chemistry. We will use state-of-the-art computer calculations to investigate chemical structures, stabilities and reactions, particularly for free radicals. Radicals are of great importance in chemistry, biology and polymer science, but are difficult to study experimentally. We will use the computer calculations to determine how ....Computational Quantum Chemistry Study of Molecular Structures, Stabilities and Reactions. Computational quantum chemistry is revolutionizing the study and practice of chemistry. We will use state-of-the-art computer calculations to investigate chemical structures, stabilities and reactions, particularly for free radicals. Radicals are of great importance in chemistry, biology and polymer science, but are difficult to study experimentally. We will use the computer calculations to determine how to make radicals more stable, how they react to produce polymers, how they cause damage to proteins, and how they are involved in helping vitamin B12 make reactions go faster. We will create new methodologies in order to reliably achieve these goals.Read moreRead less