Inhibitors Of Hypoxanthine-guanine-xanthine Phosphoribosyltransferase As Versatile Drugs To Treat Infectious Diseases
Funder
National Health and Medical Research Council
Funding Amount
$766,163.00
Summary
Due to the increase in resistance to many of the frontline drugs to treat bacterial and parasitic infections, there is an urgent need to develop new pipelines for drug discovery against the pathogens that are causative agents of this diseases. This project pioneers the blocking of nucleotide synthesis to develop new drug leads to treat malaria, human tuberculosis, African sleeping sickness, Chagas disease and uropathogenic E.coli infections.
Targeting Acetohydroxyacid Synthase To Discover New Antifungal Agents.
Funder
National Health and Medical Research Council
Funding Amount
$481,135.00
Summary
Invasive fungal infections are increasingly being recognized as a major life threatening risk to hospitalized patients. The efficacy of the current medications is sub-optimal due to the emergence of resistance and the high dosage regimes that are required to treat these infections. We propose to develop a new class of antifungal agent that target an enzyme, acetohydroxyacid synthase, whose activity is required for the survival of pathogenic fungi in mammals.
Virtual Screening In Structure-Based Drug Design For Malaria
Funder
National Health and Medical Research Council
Funding Amount
$285,000.00
Summary
Malaria continues to be one of the most serious health problems in the world today with approximately 300 million people affected and 1.5 million recorded deaths per year. The most deadly and widespread parasite responsible for this disease is Plasmodium falciparum. Because of the parasite's increasing resistance to traditional medication, there is an urgent need to develop more effective treatments. Two approaches are feasible: vaccines and new drugs. Both will probably be necessary to combat t ....Malaria continues to be one of the most serious health problems in the world today with approximately 300 million people affected and 1.5 million recorded deaths per year. The most deadly and widespread parasite responsible for this disease is Plasmodium falciparum. Because of the parasite's increasing resistance to traditional medication, there is an urgent need to develop more effective treatments. Two approaches are feasible: vaccines and new drugs. Both will probably be necessary to combat the spread and consequences of malaria. We are approaching this problem by targeting an enzyme which is essential for the survival of the parasite. All protozoan parasites make their purine nucleotides (the building blocks of DNA and RNA) by purine base salvage. Unlike humans, they cannot make purines from simple precursor molecules. The key enzyme in the salvage pathway is hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT). Our plan is to capitalize on knowledge of the precise structure of HGXPRT and the increased power of computers to determine which chemicals are able to bind tightly and specifically to the active site of the enzyme. We will then test the ability of these compounds to inhibit purified human and Plasmodium enzymes and their ability to inhibit the growth of the malarial parasite in red cells. Chemical synthesis will be used to improve the effectiveness of these compounds.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0561013
Funder
Australian Research Council
Funding Amount
$220,000.00
Summary
X-ray diffraction System for Protein Crystallography and Structural Biology. Knowledge of protein structures enables researchers to explain cellular function at a molecular level. In particular, it provides essential information to understand the mechanism of diseases, such as cancer or AIDS, and it ultimately leads to the design of better drugs.
An in-house X-ray protein crystallography facility will allow us to determine the structures of key proteins effectively and competitively, opening up ....X-ray diffraction System for Protein Crystallography and Structural Biology. Knowledge of protein structures enables researchers to explain cellular function at a molecular level. In particular, it provides essential information to understand the mechanism of diseases, such as cancer or AIDS, and it ultimately leads to the design of better drugs.
An in-house X-ray protein crystallography facility will allow us to determine the structures of key proteins effectively and competitively, opening up extensive possibilities for multi-disciplinary ground-breaking research.
The University research portfolio has evolved to embrace the revolution in structural biology with numerous projects and collaborations focusing on proteins involved in bacterial infections, degenerative disorders and biotechnological applications.Read moreRead less
The development of tools to study carbohydrate-processing enzymes implicated in human disease. Diseases caused by improper function of carbohydrate-processing enzymes are a major health burden. This research aims to find ways to restore the function of these enzymes bringing a better quality of life to people suffering from these diseases.
Understanding and exploiting bacterial sulfatases. Bacterial sulfatases participate in environmental nutrient cycling and are implicated in bacterial pathogenesis mechanisms. These enzymes catalyze the hydrolysis of sulfate esters and possess an unusual posttranslational active-site modification where a cysteine residue is oxidized to formylglycine. We will study the mechanism of these enzymes in detail and design inhibitors that exploit the reactivity of this aminoacid. This work has significan ....Understanding and exploiting bacterial sulfatases. Bacterial sulfatases participate in environmental nutrient cycling and are implicated in bacterial pathogenesis mechanisms. These enzymes catalyze the hydrolysis of sulfate esters and possess an unusual posttranslational active-site modification where a cysteine residue is oxidized to formylglycine. We will study the mechanism of these enzymes in detail and design inhibitors that exploit the reactivity of this aminoacid. This work has significance because of application to areas that include the treatment of cancer and bacterial infections. Additionally, we will clone novel carbohydrate sulfatases from the heparin-degrading bacterium Flavobacterium heparinum. These sulfatases will have use in biotechnology for characterization of sulfated glycoconjugates.Read moreRead less
Identification of functionally important autophosphorylation site(s) on ataxia telangiectasia and Rad 3 - related (ATR) protein kinase. The integrity of our genetic material must be maintained so that it can be passed on from one generation to the next and also to minimize the risk of cancer and other pathologies in an individual. There are multiple proteins involved in protecting our DNA including several enzymes that detect and signal DNA damage to a series of pathways involved in halting the ....Identification of functionally important autophosphorylation site(s) on ataxia telangiectasia and Rad 3 - related (ATR) protein kinase. The integrity of our genetic material must be maintained so that it can be passed on from one generation to the next and also to minimize the risk of cancer and other pathologies in an individual. There are multiple proteins involved in protecting our DNA including several enzymes that detect and signal DNA damage to a series of pathways involved in halting the passage of cells through the cell cycle so that repair can occur. This project studies the mechanism of action of one of these enzymes which will be of benefit in designing new compounds to fight disease. Read moreRead less
New models of mitochondrial fatty acid oxidation disorders. Mitochondrial disease can affect both children and adults and is often fatal. This project will study mitochondrial function in cell types of the heart and brain to better understand how they generate energy in these tissues. This will provide new insights into mitochondrial metabolism and how defects in this process cause mitochondrial disease.