An Investigation Of Vibrio Cholerae Sialidase As A Target For Drug Discovery
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
The prevalence of the disease Cholera still causes significant human mortality, in particular in underdevloped countries. The process that enables the cholera toxin to cause signficant damage is now partly understood. This research project will provide a range of chemical entities (probes) that have the potential of intervening in this process . These probes will be the basis for a drug discovery programme that targets toxin binding. Through molecular modelling based on protein structural inform ....The prevalence of the disease Cholera still causes significant human mortality, in particular in underdevloped countries. The process that enables the cholera toxin to cause signficant damage is now partly understood. This research project will provide a range of chemical entities (probes) that have the potential of intervening in this process . These probes will be the basis for a drug discovery programme that targets toxin binding. Through molecular modelling based on protein structural information, drug candidate synthesis and evaluation of these compounds in relevant test tube (in vitro) assays it is envisaged that a number of candidate compounds will be then further optimised for eventual pre-clinical investigation. The technology to be used in this project is comparable to that we have used in the discovery of the recently approved influenza drug, Relenza .Read moreRead less
Development Of Specific Inhibitors Of Parasitic Enzymes
Funder
National Health and Medical Research Council
Funding Amount
$199,413.00
Summary
Parasitic diseases such as malaria, schistosomiasis, filariasis, leishmaniasis, and american trypanosomiasis (Chaga?s disease) are a significant public health issue, especially in tropical and subtropical regions of the world. In children, they cause death or impaired growth and in adults debilitating chronic illness. These parasitic infections are increasingly being recognized as responsible for chronic illness in many industrialized countries as well. There are no vaccines currently available ....Parasitic diseases such as malaria, schistosomiasis, filariasis, leishmaniasis, and american trypanosomiasis (Chaga?s disease) are a significant public health issue, especially in tropical and subtropical regions of the world. In children, they cause death or impaired growth and in adults debilitating chronic illness. These parasitic infections are increasingly being recognized as responsible for chronic illness in many industrialized countries as well. There are no vaccines currently available for the treatment of any of the human parasitic infections. In addition, the drugs that are currently used are becoming less effective because of the spread of drug resistant strains. Schistosomiasis, is the second most prevalent parasitic disease, after malaria, and is a leading cause of severe morbidity and death in many parts of the world. The disease is caused by flatworms or blood flukes, the eggs of which indirectly cause damage to the liver and spleen of infected individuals. These parasites feed on human red blood cells and use hemoglobin as their major food source. Our collaborative team (Brindley, Abbenante, Fairlie) has identified two enzymes that these flatworms need to use to eat red blood cells. This project aims to develop compounds that will stop these enzymes from functioning. These compounds will be tested to see whether they can cause the parasites to die of starvation. If successful these new compounds can be used as drugs to treat the disease and the general strategy can be applied to other blood-feeding parasites.Read moreRead less
Vancomycin Derivatives Active Against Resistant Bacterial Nosocomial Infections
Funder
National Health and Medical Research Council
Funding Amount
$760,763.00
Summary
Bacterial infection is a leading cause of death worldwide and the emergence of superbugs that are resistant to multiple treatments is becoming a major global concern. Vancomycin is the drug of last resort for the treatment of hospital-acquired Gram -positive bacterial infections. We will synthetically modify vancomycin by incorporating naturally occurring membrane-associative peptides to produce novel antibiotics with multiple modes of action to avoid existing bacterial resistance mechanisms.
Development Of Novel Hybrid Antibiotics For The Treatment Of Hospital And Community Acquired Drug Resistant Gram-Negative And Gram-Postitive Bacterial Infections
Funder
National Health and Medical Research Council
Funding Amount
$715,076.00
Summary
Drug resistant bacteria now pose a serious and growing threat to human health. Many bacteria have developed new resistance mechanisms such that most common antibiotics no longer can protect patients from serious, life-threatening infection. We will modify two existing antibiotics, colistin and carbapenem (a penicillin), to convert it into a more powerful antibiotic that targets resistant bacteria.
Given that consumption of flavonoids in the diet is likely to be 100-1000 mg per day, it is important to find out how flavonoids might influence GABA-A receptors especially in relation to influencing actions of other therapeutic agents that interact with GABA-A receptors in the brain, such as benzodiazepines and ethanol. This may lead to new strategies in the use of herbal medicines and their possible interactions with other medications. These studies will provide information on how key dietary ....Given that consumption of flavonoids in the diet is likely to be 100-1000 mg per day, it is important to find out how flavonoids might influence GABA-A receptors especially in relation to influencing actions of other therapeutic agents that interact with GABA-A receptors in the brain, such as benzodiazepines and ethanol. This may lead to new strategies in the use of herbal medicines and their possible interactions with other medications. These studies will provide information on how key dietary flavonoids and novel structurally related chemicals could influence brain function. This project will probe the chemical characteristics of novel modes of action of flavonoid-related compounds in order to design and develop potentially useful therapeutic agents for CNS disorders involving GABA-A receptors. It is likely that flavonoids act on specific sites on such receptors that represent important new targets for drug development. This research is intended to provide new chemical entities useful as either alternatives to the benzodiazepines, which have a range of undesirable side effects, or as adjuncts to enable reduced doses of benzodiazepines to be used.Read moreRead less
Pharmacology Of Potential Anti-Tumour Agents: Iron Chelators Of The BpT Class
Funder
National Health and Medical Research Council
Funding Amount
$585,455.00
Summary
Pharmacology of Potential Anti-Tumour Agents: Iron Chelators of the BpT Class Cancer cells have a high iron requirement for DNA synthesis and many clinical trials showed Fe chelators are effective anti-cancer drugs. Their potential to act as anti-tumour agents has been confirmed by the entrance of Triapine into widespread NCI clinical trials. In this NHMRC Renewal, we will perform pharmacological and preclinical studies to promote the development of BpT chelators as novel anti-tumour agents.
Cage Compounds As Blockers Of GABA And Glycine Receptor-channels
Funder
National Health and Medical Research Council
Funding Amount
$519,000.00
Summary
GABA and glycine are the major inhibitory neurotransmitters in the brain and, together with their associated receptors (GABARs and GlyRs), they are responsible for rapid inhibitory neurotransmission. The importance of these receptors in brain function and dysfunction is emphasized by their implication in a number of hereditary and more complex disorders, such as anxiety, epilepsy, dementias, alcoholism and lack of motor control. Many compounds act on these receptor-channels and modulate their fu ....GABA and glycine are the major inhibitory neurotransmitters in the brain and, together with their associated receptors (GABARs and GlyRs), they are responsible for rapid inhibitory neurotransmission. The importance of these receptors in brain function and dysfunction is emphasized by their implication in a number of hereditary and more complex disorders, such as anxiety, epilepsy, dementias, alcoholism and lack of motor control. Many compounds act on these receptor-channels and modulate their function and some of these are used clinically (e.g., anti-anxiolytics, some anaesthetics). Recently, some compounds which inhibit these receptor-channels (typically convulsant drugs) have, in low doses, been shown to enhance learning and memory and to provide some improvement in different senile dementias. Ginkgo biloba extract is used worldwide and has been shown to be effective in the symptomatic treatment of cognitive disorders associated with old age dementia and Alzheimer's disease. Some of the active constituents, the ginkgo compounds, inhibit the GABA and glycine receptors but, importantly for therapeutic activity, are not convulsants. It is suspected that these and related compounds bind within the pore of these receptor-channels to mediate their inhibition, although the data is conflicting and no-one precisely knows how they act. This project aims to directly investigate how the ginkgo compounds, and the related compound picrotoxinin, act on the GABA and glycine receptors, and to determine the site on the protein to which they bind. Furthermore, this project will shed some light on why picrotoxin is a convulsant but the gingko compounds are not. A more thorough understanding of exactly how these compounds work will give us important information on how these receptor-channels work and will lead to the development of better therapeutics, particularly those targeted against old-age dementias and Alzheimers disease.Read moreRead less
Structure-based Design Of Inhibitors Of Oxidative Protein Folding In Enterobacteriaceae.
Funder
National Health and Medical Research Council
Funding Amount
$523,540.00
Summary
Antibiotic resistance represents a major public health problem. For gram-negative bacteria in particular, the situation is increasingly bleak, with the accumulation of resistance to existing drugs and few if any new drugs in the pipeline. We are using structure-based drug design to develop novel strategies for the treatment of gram-negative bacterial infections.