Design And Development Of Inhibitors Of The Dengue Virus Protease As Antiviral Drugs
Funder
National Health and Medical Research Council
Funding Amount
$362,513.00
Summary
Dengue viruses are carried by mosquitoes and infect millions of people around the world, particularly in tropical countries of SE Asia, Central and South America, Africa and recently in Australia (North Queensland and NT). There is no vaccine or drug available for preventing or treating the infections, which are characterised by severe illness that involves inflammation and fevers that can sometimes be fatal. This proposal focuses on a virus specific enzyme. This enzyme (called a protease) is es ....Dengue viruses are carried by mosquitoes and infect millions of people around the world, particularly in tropical countries of SE Asia, Central and South America, Africa and recently in Australia (North Queensland and NT). There is no vaccine or drug available for preventing or treating the infections, which are characterised by severe illness that involves inflammation and fevers that can sometimes be fatal. This proposal focuses on a virus specific enzyme. This enzyme (called a protease) is essential for the virus to multiply and so it is a potential target for new drugs that can bind to it and block its function. We have produced and purified this viral enzyme in the laboratory and now propose to design, synthesize, and develop the first drugs for the treatment of humans infected with dengue virus. We plan to do this by examining the action of the enzyme, determining its three dimensional structure, and using computers and chemical methods to obtain very powerful blockers of enzyme action. These drug candidates will be tested against the enzyme, against cells infected with virus, and in rats to find out if they can be administered by mouth or by injection and if they have any toxic side effects. This project will provide valuable information about how to develop drugs to stop dengue fever and its associated illnesses.Read moreRead less
A Bioinformatic Analysis And Structural Study On The Inositol Polyphosphate 5-phosphatases
Funder
National Health and Medical Research Council
Funding Amount
$421,320.00
Summary
Communication (or signaling) inside the cell enables the cell to respond to factors in its external environment, such as hormones or growth factors. The inositol phosphates and the phosphoinositides are signaling molecules that play an essential role in intracellular communication. The 5-phosphatases are able to modify these molecules and terminate, and in certain cases stimulate, signals. Failure to properly control intracellular signaling pathways may result in abnormal cell growth and cancer. ....Communication (or signaling) inside the cell enables the cell to respond to factors in its external environment, such as hormones or growth factors. The inositol phosphates and the phosphoinositides are signaling molecules that play an essential role in intracellular communication. The 5-phosphatases are able to modify these molecules and terminate, and in certain cases stimulate, signals. Failure to properly control intracellular signaling pathways may result in abnormal cell growth and cancer. Human 5-phosphatases are a complex family of enzymes: In addition to the region responsible for phosphatase activity (the catalytic domain) many members contain other protein modules . These associated domains may perform critical roles, such as regulating intracellular location and docking with other proteins. This project aims to perform a computational investigation of human 5-phosphatases and their associated domains. In particular we will search for novel phosphatases, investigate the evolutionary relationships between members of each domain family, and make testable predictions regarding the function of uncharacterized domains. This study will take advantage of data produced by the recently completed human genome project. The second aim of the project is to determine, using X-ray crystallography, the three-dimensional shape (or atomic structure) of a representative member of the 5-phosphatase family. Solving the structure of a 5-phosphatase at the atomic level is critical for understanding the nature of substrate specificity and for rational drug design.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