Total chemical synthesis of a redesigned enzyme, HIV-1 PR, containing an artificial tunable catalytic apparatus. The research project proposed represents a novel approach using total chemical synthesis to study the enzyme action of the HIV-1 PR, an aspartyl protease essential for the replication of AIDS virus. The redesign of the catalytic apparatus will allow us to investigate molecular aspects of its action. The synthetic polypeptide chain will be folded and characterised for the correct folde ....Total chemical synthesis of a redesigned enzyme, HIV-1 PR, containing an artificial tunable catalytic apparatus. The research project proposed represents a novel approach using total chemical synthesis to study the enzyme action of the HIV-1 PR, an aspartyl protease essential for the replication of AIDS virus. The redesign of the catalytic apparatus will allow us to investigate molecular aspects of its action. The synthetic polypeptide chain will be folded and characterised for the correct folded structure by NMR, and assayed for enzymatic activity. It can be expected that significant new insights into the molecular basis of the properties of the HIV-1 PR will be obtained. This will be an important contribution to biomedical research.Read moreRead less
The Synthesis and Pharmacological Evaluation of Novel Bivalent Dopamine D2 and Adenosine A2A Ligands for the Treatment of Parkinson's Disease. This program will significantly contribute to the training of highly qualified personnel in the area of organic and medicinal chemistry where there is currently a national shortage. Other benefits are the capacity to advance this critical research in PD and potentially provide substantial national competitive advantages and growth opportunities in the glo ....The Synthesis and Pharmacological Evaluation of Novel Bivalent Dopamine D2 and Adenosine A2A Ligands for the Treatment of Parkinson's Disease. This program will significantly contribute to the training of highly qualified personnel in the area of organic and medicinal chemistry where there is currently a national shortage. Other benefits are the capacity to advance this critical research in PD and potentially provide substantial national competitive advantages and growth opportunities in the global anti-Parkinsonian therapeutics market.Read moreRead less
Applications of the Polonovski Reaction in the Synthesis of Bioactive Opiates. This program will contribute to the training of highly qualified personnel in the area of organic and medicinal chemistry. It will also address the development of improved processes for the large scale preparation of semi-synthetic pharmaceutical opiates in support of one of Australia's important export industries. Furthermore, a greater understanding of the structure-activity relationships of noscapine will make a ....Applications of the Polonovski Reaction in the Synthesis of Bioactive Opiates. This program will contribute to the training of highly qualified personnel in the area of organic and medicinal chemistry. It will also address the development of improved processes for the large scale preparation of semi-synthetic pharmaceutical opiates in support of one of Australia's important export industries. Furthermore, a greater understanding of the structure-activity relationships of noscapine will make a contribution to the overall search for improved anti-cancer agents.Read moreRead less
CHARACTERISATION OF NOVEL BIOACTIVES FROM AUSTRALIAN HONEY WITH THERAPEUTIC POTENTIAL. Honey from specific Australian flowering plants has been identified that contain significant therapeutic properties in wound healing and other treatments. The research project proposed will identify and fully characterise the bioactive components of selected Australian honey (Medihoney) with antibiotic and growth promoting activites. These aims will be supported by high resolution mass spectrometry interfaced ....CHARACTERISATION OF NOVEL BIOACTIVES FROM AUSTRALIAN HONEY WITH THERAPEUTIC POTENTIAL. Honey from specific Australian flowering plants has been identified that contain significant therapeutic properties in wound healing and other treatments. The research project proposed will identify and fully characterise the bioactive components of selected Australian honey (Medihoney) with antibiotic and growth promoting activites. These aims will be supported by high resolution mass spectrometry interfaced with HPLC and or affinity chip surfaces, 750 MHz NMR analysis and a range of relevant bioassays on specific organisms and cell lines. These outcomes will not only enhance the value of current honey-based products but have the potential to identify new therapeutic lead molecules.Read moreRead less
Inhibitors of enzymes in the lysine biosynthetic pathway. Recent reports of increasing bacterial resistance to antibiotics highlight the need for continual development of new antibacterial agents. Inhibitors of the biosynthesis of the amino acid lysine - an essential component of bacterial proteins and cell wall - may provide a novel class of antibiotics. This project describes investigations of the mechanism of the first two enzymes in the lysine biosynthetic pathway and the design and synthesi ....Inhibitors of enzymes in the lysine biosynthetic pathway. Recent reports of increasing bacterial resistance to antibiotics highlight the need for continual development of new antibacterial agents. Inhibitors of the biosynthesis of the amino acid lysine - an essential component of bacterial proteins and cell wall - may provide a novel class of antibiotics. This project describes investigations of the mechanism of the first two enzymes in the lysine biosynthetic pathway and the design and synthesis of inhibitors of these enzymes.Read moreRead less
High Pressure and Fluorous Approaches to Fostriecin Libraries: New Therapeutic Opportunities. The natural product, Fostriecin, displays considerable broad-spectrum anti-cancer activity, acting via a novel mechanism. However, this activity is tempered by its considerable instability, being too unstable to be used as a therapeutic agent. Using state-of-the-art approaches we will, rapidly generate libraries of more stable and biologically active fostriecin analogues and examine their potential to b ....High Pressure and Fluorous Approaches to Fostriecin Libraries: New Therapeutic Opportunities. The natural product, Fostriecin, displays considerable broad-spectrum anti-cancer activity, acting via a novel mechanism. However, this activity is tempered by its considerable instability, being too unstable to be used as a therapeutic agent. Using state-of-the-art approaches we will, rapidly generate libraries of more stable and biologically active fostriecin analogues and examine their potential to be used anti-cancer agents. This project represents an opportunity for Australia to take a significant, innovative lead in the development of hitherto unforseen therapeutic agents.Read moreRead less
The Design of New Integrase Inhibitors Targeting HIV-1. There is still no cure in sight for the worldwide HIV pandemic and the worsening viral resistance problem creates a need to find new and novel compounds for therapeutic use. This project aims to design and synthesize new anti-HIV drugs by targeting two separate enzymes within the HIV life-cycle. This 'dual-action' approach of designing a single molecular scaffold to target separate enzymes would enable a synergistic effect while minimizing ....The Design of New Integrase Inhibitors Targeting HIV-1. There is still no cure in sight for the worldwide HIV pandemic and the worsening viral resistance problem creates a need to find new and novel compounds for therapeutic use. This project aims to design and synthesize new anti-HIV drugs by targeting two separate enzymes within the HIV life-cycle. This 'dual-action' approach of designing a single molecular scaffold to target separate enzymes would enable a synergistic effect while minimizing development costs. The expected outcomes from this medicinal chemistry project include the discovery of new compounds with the potential for further development as therapeutic agents against HIV.Read moreRead less
Structure-based discovery of anti-rotaviral agents. Rotavirus causes, particularly in children under 5 years of age, significant loss of life worldwide. Over 600,000 children under 5 years of age per annum die as a result of rotavirus infection. Australia records over 10,000 hospitalisations per annum due to rotavirus infection. This project aims, using structure-based drug design techniques, to develop inhibitors of a rotavirus protein that is essential in its lifecycle. These inhibitors may ....Structure-based discovery of anti-rotaviral agents. Rotavirus causes, particularly in children under 5 years of age, significant loss of life worldwide. Over 600,000 children under 5 years of age per annum die as a result of rotavirus infection. Australia records over 10,000 hospitalisations per annum due to rotavirus infection. This project aims, using structure-based drug design techniques, to develop inhibitors of a rotavirus protein that is essential in its lifecycle. These inhibitors may lead to the development of useful drugs to treat rotavirus infection and may reduce significant loss of life caused by this deadly virus.Read moreRead less
The Design and Development of the Next Generation Anti-HIV Drugs. This medicinal chemistry project will develop new computer-aided modelling techniques for drug design and development and will then apply them to the design of new therapeutics for the treatment of HIV-1/AIDS. Once developed, these new techniques can also be applied to other disease targets including various cancers, where specific proteins have been identified as causative. This research will also contribute to the education of y ....The Design and Development of the Next Generation Anti-HIV Drugs. This medicinal chemistry project will develop new computer-aided modelling techniques for drug design and development and will then apply them to the design of new therapeutics for the treatment of HIV-1/AIDS. Once developed, these new techniques can also be applied to other disease targets including various cancers, where specific proteins have been identified as causative. This research will also contribute to the education of young scientists, training them in cutting-edge research skills.Read moreRead less
Structure-based discovery of anti-parainfluenza viral agents. Respiratory diseases, for example croup and bronchitis, in children are caused in the main by human parainfluenza viruses (hPIVs) types 1-3. No vaccines or specific antiviral therapy against hPIV infections exist. This project targets an essential protein in the virus' lifecycle. The essential triple role of the protein in virus spread makes it an attractive target for the development of hPIV-specific drugs. This project aims to prod ....Structure-based discovery of anti-parainfluenza viral agents. Respiratory diseases, for example croup and bronchitis, in children are caused in the main by human parainfluenza viruses (hPIVs) types 1-3. No vaccines or specific antiviral therapy against hPIV infections exist. This project targets an essential protein in the virus' lifecycle. The essential triple role of the protein in virus spread makes it an attractive target for the development of hPIV-specific drugs. This project aims to produce lead-like compounds that inhibit the protein's function and may provide novel drug candidates for further development. Furthermore the role of human host cell-associated carbohydrates in parainfluenza infection will be better understood.Read moreRead less