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Cryptococcal Phospholipases: Structure, And Potential Targets For Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$511,650.00
Summary
Mortality and morbidity from invasive fungal infections have increased substantially over the past two decades, especially in immunocompromised patients, such as those with AIDS. Antifungal drugs marketed at present are not very effective or are toxic. There is a need to identify new metabolic and structural targets, some of which are responsible for fungal virulence, as potential areas for development of new drugs. One such virulence factor discovered in our laboratory is an enzyme secreted by ....Mortality and morbidity from invasive fungal infections have increased substantially over the past two decades, especially in immunocompromised patients, such as those with AIDS. Antifungal drugs marketed at present are not very effective or are toxic. There is a need to identify new metabolic and structural targets, some of which are responsible for fungal virulence, as potential areas for development of new drugs. One such virulence factor discovered in our laboratory is an enzyme secreted by the pathogenic fungus, Cryptococcus neoformans, which is acquired by inhalation into the lungs where it can cause lesions, and eventually spreads to other parts of the body, including the brain (median mortality, 17%). This enzyme breaks down cell membranes, aiding invasion into the host lungs and other tissues, and is called phospholipase B (PLB). It is also produced by several other pathogenic fungi, and is different from human phospholipases. In this project we aim to understand how the PLB is constructed, so that we can work out where the cell membrane components bind to it. We will then design drugs which can bind to the PLB enzyme in place of membrane components and in this way block its harmful effects. We will test the effects of such drugs to make sure they do not interfere with human enzyme systems. Inhibitory compounds may also be able to kill the cryptococcal cells, especially if administered together with currently used therapies. Drugs developed to treat Cryptococcus will then be applicable to other systemic fungal infections - a major advance in the treatment of fungal disease, and a saving of some A$60,000 per patient (estimated from a recent U.S. study).Read moreRead less
Design And Evaluation Of Inhibitors Of Phospholipases A2 As Anti-Inflammatory Drugs
Funder
National Health and Medical Research Council
Funding Amount
$317,545.00
Summary
There are at least 16 types of enzymes called phospholipases A2 (PLA2). They are found in venoms of snakes, bees, lizards, cone snails, etc and act as toxic and digestive agents. PLA2 enzymes are also found in cells and tissues of mammals where they carry out a wide range of digestive, maintenance, immune defence, and cell signalling functions. The human pancreas secretes one form of PLA2 into the gut to aid digestion. Human immune cells (macrophages, thymocytes, spleen leukocytes, platelets) us ....There are at least 16 types of enzymes called phospholipases A2 (PLA2). They are found in venoms of snakes, bees, lizards, cone snails, etc and act as toxic and digestive agents. PLA2 enzymes are also found in cells and tissues of mammals where they carry out a wide range of digestive, maintenance, immune defence, and cell signalling functions. The human pancreas secretes one form of PLA2 into the gut to aid digestion. Human immune cells (macrophages, thymocytes, spleen leukocytes, platelets) use other forms of PLA2 in the inflammatory immune response to kill infectious foreign agents like viruses and bacteria. One form of PLA2, known as type IIa, is the main bacteria-killing ingredient of human tears and it is also a chief component of fluid from the joints of patients with arthritis. Type IIa PLA2 is present in abnormally high levels in blood from humans with arthritis, burns, sepsis, ARDS, atherosclerosis, Crohn's disease, malaria, cancer and other chronic illnesses. These high levels can cause injury, tissue damage and pain due to too much inflammation and treatments are needed to stop or decrease effects of this enzyme . For these reasons this and related enzymes are thought to be potential targets for drugs which would act by blocking the functions of such an enzyme. Our group has been using computers to design new chemicals that can selectively fit into this enzyme and stick very tightly. We are determining the three dimensional structures of these chemicals in the enzyme to learn how to make them bind even more tightly. This information is allowing us to synthesize new selective drugs that stop PLA2 from promoting the development of disease. We propose to continue these studies towards developing powerful new antiinflammatory drugs that block the enzyme, and to demonstrate possible benefits of these drugs by testing them in animal models of arthritis, sepsis, adult respiratory distress syndrome (ARDS), period pain, malaria, and cancer.Read moreRead less
Evolution And Targeting Of Polysaccharide Biosynthesis In Leishmania Parasites
Funder
National Health and Medical Research Council
Funding Amount
$449,484.00
Summary
Leishmania are parasitic protozoa that cause devastating diseases in humans. This proposal will identify the enzymes involved in the biosynthesis of an unusual carbohydrate reserve material that accumulates in pathogenic stages of these parasites. Information on the structure and mode of action of these enzymes will be used to develop novel drugs that will be tested for anti-parasite activity.
Analysis Of The Plasmodium Falciparum M18 Aspartyl Aminopeptidase
Funder
National Health and Medical Research Council
Funding Amount
$613,683.00
Summary
Malaria remains a major cause of death and disease in many parts of the world. There is widespread resistance to all currently used drugs and an urgent need for new treatmants. We have identified the malaria enzyme, aspartyl aminopeptidase as a new drug target. This proposal will investigate the biological role of this enzyme and has the potential to identify new compounds which may be effective antimalarial drugs.
Structure And Gene Regulation Of Human Glutathione Transferase GSTT1-1
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Glutathione transferases (GSTs) play a critical role cellular detoxification system. They belong to the phase II enzymes of the xenobiotic metabolism and conjugate a wide range of drugs and chemicals with glutathione to increase water solubility and thereby enhancing their elimination. The conjugation with glutathione is considered an important detoxification route for most chemicals. However, it has been shown that in many cases this pathway leads to metabolites that are more toxic than the ini ....Glutathione transferases (GSTs) play a critical role cellular detoxification system. They belong to the phase II enzymes of the xenobiotic metabolism and conjugate a wide range of drugs and chemicals with glutathione to increase water solubility and thereby enhancing their elimination. The conjugation with glutathione is considered an important detoxification route for most chemicals. However, it has been shown that in many cases this pathway leads to metabolites that are more toxic than the initial chemical or drug. The gene deletion of the particular human GSTT1 gene results in total loss of this particular enzyme activity in all tissues of homozygous null genotype individuals. This phenotype is called non-conjugator . Non-conjugators seem to have a higher risk to develop certain cancer types, e.g. urinary bladder cancer or brain tumours, while they seem to be less susceptible for others, e.g. liver. Occupational exposure to chemicals is of relevance in such relationships because the GSTT1 enzyme metabolises a wide range of industrial chemicals including solvents but also monomers used in the production of rubbers and other polymers. In addition, GSTT1 seems to influence the efficay of cancer chemotherapy by inactivating certain anti-cancer drugs, eg. BCNU, that is predominantly use in treatment of brain tumours. The aims of this study include the characterisation of the tissue-specific activity and the influence of xenobiotics on the protein levels of this enzyme. The study leads to a better understanding of the etiology of exposure related cancers and of the mechanisms of resistance to cancer chemotherapy. Such knowledge allows the development of concepts for the optimisation of efficacy and minimisation of side effects in chemotherapy.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.
Inhibitors Of Biotin Protein Ligase: A New Class Of Antibiotic Targetting Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$605,963.00
Summary
The rise of drug-resistant "superbugs" is a major healthcare concern in hospitals around the world. New antibiotics are needed to combat infections caused by bacteria that are resistant to current drugs. One collaborative team of researchers is addressing this issue. They have discovered a new drug effective against Staphylococcus aureus, the cause of Golden Staph using a combination of scientific disciplines the team is now moving forward and improving their exciting new drug.