Understanding the cardioprotective effects of flavonols. Heart attack and stroke are a major cause of death and disablement in Australia. Current therapies do not treat the underlying causes of these diseases. In this project we will investigate a promising new drug treatment for these diseases and will determine how this poorly understood drug acts to reduce damage to the heart. This project will lead to new treatments for cardiovascular diseases and will enhance our understanding of the causes ....Understanding the cardioprotective effects of flavonols. Heart attack and stroke are a major cause of death and disablement in Australia. Current therapies do not treat the underlying causes of these diseases. In this project we will investigate a promising new drug treatment for these diseases and will determine how this poorly understood drug acts to reduce damage to the heart. This project will lead to new treatments for cardiovascular diseases and will enhance our understanding of the causes of these disease states.Read moreRead less
Interrogating diarylquinoline toxicity with targeted organic synthesis. Bedaquiline is the only new first-line treatment with a new mechanism of action to treat TB in the last 40 years, approved by the FDA on 31 December 2012. Alarmingly, this compound, has significant toxicities. The hypothesis tested in this project is that decreasing lipophilicity and basicity in this class of compounds while retaining target affinity will decrease toxicity but retain anti-TB activity. The project aims to: sy ....Interrogating diarylquinoline toxicity with targeted organic synthesis. Bedaquiline is the only new first-line treatment with a new mechanism of action to treat TB in the last 40 years, approved by the FDA on 31 December 2012. Alarmingly, this compound, has significant toxicities. The hypothesis tested in this project is that decreasing lipophilicity and basicity in this class of compounds while retaining target affinity will decrease toxicity but retain anti-TB activity. The project aims to: synthesise novel heteroarylalkylamines distinct from bedaquiline and designed to be more polar, less basic, and metabolically more stable; and, test all successfully synthesised target compounds for mechanism-based anti-tuberculosis activity, hERG-mediated cardiotoxicity, metabolic instability, and phospholipidosis.Read moreRead less
Mannosyl transfer processes in leishmania and mycobacteria. The human diseases leishmaniasis and tuberculosis are caused by infectious microorganisms. We will target pathways to the biosynthesis and degradation of parasite-specific mannose containing metabolites that play essential roles in the ability of these pathogens to cause disease. We will develop new ways to study these pathways, and will synthesize novel substrates and inhibitors that will allow the development of antituberculosis and a ....Mannosyl transfer processes in leishmania and mycobacteria. The human diseases leishmaniasis and tuberculosis are caused by infectious microorganisms. We will target pathways to the biosynthesis and degradation of parasite-specific mannose containing metabolites that play essential roles in the ability of these pathogens to cause disease. We will develop new ways to study these pathways, and will synthesize novel substrates and inhibitors that will allow the development of antituberculosis and antileishmanial drugs. This project will contribute to our national competitiveness in the newly emerging area of chemical biology.Read moreRead less
Mannose metabolism in pathogenic microorganisms. Current treatments for tuberculosis and leishmaniasis are failing due to chronic underinvestment by the private sector and public agencies over many decades. The causative agents, the microorganisms Leishmania spp and Mycobacterium tuberculosis, respectively, use sugar processing pathways that differ from humans, and thus represent targets for new drugs. We will study two related sugar-processing biochemical pathways in these organisms. We will de ....Mannose metabolism in pathogenic microorganisms. Current treatments for tuberculosis and leishmaniasis are failing due to chronic underinvestment by the private sector and public agencies over many decades. The causative agents, the microorganisms Leishmania spp and Mycobacterium tuberculosis, respectively, use sugar processing pathways that differ from humans, and thus represent targets for new drugs. We will study two related sugar-processing biochemical pathways in these organisms. We will develop new ways to measure enzyme activity using mass spectrometry, and new reagents to clone several biosynthetic enzymes. Our work will lay a foundation for new antibiotics to combat these insidious diseases, and will foster Australian expertise in chemical biology and innovative basic science.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
Allosteric modulators as novel probes of G-Protein coupled receptor function. This research will provide novel mechanistic understanding on the function of one of the largest protein families in the mammalian genome, and the most important family with respect to drug targets. The insights gained thus have direct relevance to drug discovery. The discovery of novel G protein-coupled receptor (GPCR) allosteric enhancers will not only lead to potentially new therapeutic agents, but can significant ....Allosteric modulators as novel probes of G-Protein coupled receptor function. This research will provide novel mechanistic understanding on the function of one of the largest protein families in the mammalian genome, and the most important family with respect to drug targets. The insights gained thus have direct relevance to drug discovery. The discovery of novel G protein-coupled receptor (GPCR) allosteric enhancers will not only lead to potentially new therapeutic agents, but can significantly value-add to other national research efforts focusing on GPCR structural biology.Read moreRead less
Discovery and development of novel insulin sensitising compounds for the treatment of Type 2 diabetes. Diabetes is one of the major health problems facing Australia today, and current treatments are proving inadequate to combat this disease. We previously discovered a new drug with potential for development for the treatment of diabetes. In this project, we will identify how this drug works to combat diabetes in cell and animal models, and use novel chemistry approaches to modify the drug to imp ....Discovery and development of novel insulin sensitising compounds for the treatment of Type 2 diabetes. Diabetes is one of the major health problems facing Australia today, and current treatments are proving inadequate to combat this disease. We previously discovered a new drug with potential for development for the treatment of diabetes. In this project, we will identify how this drug works to combat diabetes in cell and animal models, and use novel chemistry approaches to modify the drug to improve its properties and reduce potential side-effects. The outcomes of this project will be understanding of a new biological process that contributes to the development of diabetes, and the discovery and characterisation of new chemical compounds that could be developed as drugs to treat diabetes.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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100226
Funder
Australian Research Council
Funding Amount
$424,000.00
Summary
Advanced molecular discovery and characterisation facility. Natural product drug discovery in Australia requires access to high throughput functional assays to guide the separation and of novel bioactives with therapeutic potential. By establishing the advanced molecular discovery and characterisation facility in an academic environment across two institutions, research programs in early drug lead discovery and characterisation will be accelerated. It will provide unique capabilities not curren ....Advanced molecular discovery and characterisation facility. Natural product drug discovery in Australia requires access to high throughput functional assays to guide the separation and of novel bioactives with therapeutic potential. By establishing the advanced molecular discovery and characterisation facility in an academic environment across two institutions, research programs in early drug lead discovery and characterisation will be accelerated. It will provide unique capabilities not currently available in Australia, and help Australian researchers remain internationally competitive in breakthrough science and frontier technologies. The research enabled by this facility will lead to development of new drug candidates by the emerging Australian biotechnology industry.Read moreRead less
New approaches to inhibition of activity of HIV integrase. This project aims to assist in the development of novel anti-HIV drugs that will benefit the 17000 Australians and more than 33 million people worldwide who are currently suffering with this terrible disease. The project will utilise state-of-the-art approaches in structure-based drug design to identify and synthesise compounds as leads for the development of anti-HIV drugs. Furthermore, the project will provide invaluable training for t ....New approaches to inhibition of activity of HIV integrase. This project aims to assist in the development of novel anti-HIV drugs that will benefit the 17000 Australians and more than 33 million people worldwide who are currently suffering with this terrible disease. The project will utilise state-of-the-art approaches in structure-based drug design to identify and synthesise compounds as leads for the development of anti-HIV drugs. Furthermore, the project will provide invaluable training for the researchers involved and enhance the relationship between the academic and commercial collaborators.Read moreRead less