Enhancing The Cardioprotective Effect Of Diadenosine Tetraphosphate: Designing Inhibitors Against Ap4A Hydrolase
Funder
National Health and Medical Research Council
Funding Amount
$442,500.00
Summary
Ischemia describes the condition where blood flow in the blood vessels of the heart is decreased or blocked, preventing delivery of oxygen and nutrients to the heart. Ischemic preconditioning is a phenomenon where short bursts of ischemia, followed by reperfusion, actually protect the heart from a subsequent longer period of ischemia. The biochemical signalling events involved in preconditioning are complex and incompletely defined, but most likely involve multiple pathways, although the mitocho ....Ischemia describes the condition where blood flow in the blood vessels of the heart is decreased or blocked, preventing delivery of oxygen and nutrients to the heart. Ischemic preconditioning is a phenomenon where short bursts of ischemia, followed by reperfusion, actually protect the heart from a subsequent longer period of ischemia. The biochemical signalling events involved in preconditioning are complex and incompletely defined, but most likely involve multiple pathways, although the mitochondrial ATP-dependent potassium channel may be in common with most pathways. Pretreatment with the compound diadenosine tetraphosphate (Ap4A) mimics ischemic preconditioning with noticeable reductions in tissue necrosis (cell death). This treatment has been shown in experimental work to protect the heart during periods of stress such as in heart surgery or recovery from an ischemic event. The biological site of action by Ap4A may be the mitochondria ATP-dependent potassium channel or an associated protein. Ap4A can be degraded by enzymes located inside and on the outside of heart cells, notably by two forms of Ap4A hydrolase. We will use antibody assays to understand the specific localization and amount of Ap4A hydrolase before and after ischemia and after ischemic preconditioning in human heart muscle and blood vessels. We propose to determine the structure of the enzyme and use novel computer methods to screen databases for potential inhibitors. These inhibitors of Ap4A hydrolase activity could aid the design of a potent inhibitor that would prevent Ap4A hydrolase from degrading Ap4A and therefore enhance the cardioprotective properties of Ap4A as well as minimizing side effects from the break down of Ap4A. We will also use these inhibitors and other known non-degradable Ap4A analogues in bioassays to test the relative significance of Ap4A hydrolase present in different cellular locations.Read moreRead less
Plasmin is a complex enzyme that performs major roles in removal of blood clots, wound healing and in tumor metastasis. Here we will understand how plasmin function is regulated at the molecular level. These key insights will be of future use in the development of therapeutics targeting the plasmin system in cancer and clotting diseases.
Effector Export In P. Falciparum Infected Human Erythrocytes
Funder
National Health and Medical Research Council
Funding Amount
$1,066,920.00
Summary
We will investigate malaria, a parasitic disease that kills over 450,000 people a year. We will explore how the parasite identifies, invades and remodels the host cells in which it lives, scavenging nutrients and hiding from the immune system. We will characterize the proteins involved in these critical events, as they are potential targets for drugs. We will study how parasites cause disease and how the host responds to infection.
Activation And Inhibition Of The Plasminogen/Plasmin System
Funder
National Health and Medical Research Council
Funding Amount
$800,663.00
Summary
Plasmin is crucial enzyme present in blood plasma that functions in clot dissolution, inflammation, tissue remodeling, and wound healing. We aim to study how this enzyme system is controlled, by studying its interaction with receptors, co-factors and inhibitors. The information we gain will help drive the development of new generation therapeutics for the fine control of plasmin function in clotting disease, bleeding and inflammation.
Towards A New Class Of Reverse Transcriptase Inhibitor For HIV Prevention
Funder
National Health and Medical Research Council
Funding Amount
$688,833.00
Summary
There remains an urgent need for new HIV prevention strategies. New HIV drugs that block the virus by distinct ways are needed to prevent transmission of drug resistant HIV. This study seeks to identify very small molecules called “fragments” that bind to previously undiscovered pockets on the HIV reverse transcriptase to stop its function, and that can be used as building blocks to design more potent HIV drugs to be used solely for HIV prevention.
Structural And Functional Studies On The Interaction Between Alpha2-Antiplasmin And Plasmin
Funder
National Health and Medical Research Council
Funding Amount
$280,400.00
Summary
Fibrinolysis is the process by which the body dissolves clots. In this proposal we aim to investigate how the fibrinolysis inhibitor alpha2-antiplasmin interacts with the clot dissolving protease enzyme plasmin. These data will be useful for developing new approaches to accelerate plasmin-mediated clot breakdown.
Function And Inhibition Of Plasmepsin V In Targeting Malaria Virulence Proteins Into Human Erythrocytes
Funder
National Health and Medical Research Council
Funding Amount
$407,845.00
Summary
Malaria parasites dramatically renovate infected erythrocytes to survive and evade the host immune system by delivering hundreds of exported parasite proteins into the cell. The parasite protease Plasmepsin V is essential for protein export. We aim to develop potent inhibitors of this protease in the hope of blocking its function and killing the parasite. We also aim to discover the components of the trafficking pathway after cleavage by Plasmepsin V that sorts virulence proteins to the host cel ....Malaria parasites dramatically renovate infected erythrocytes to survive and evade the host immune system by delivering hundreds of exported parasite proteins into the cell. The parasite protease Plasmepsin V is essential for protein export. We aim to develop potent inhibitors of this protease in the hope of blocking its function and killing the parasite. We also aim to discover the components of the trafficking pathway after cleavage by Plasmepsin V that sorts virulence proteins to the host cell.Read moreRead less
Mechanisms Underlying APOBEC3G Restriction Of HIV-1
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
In the fight against worldwide HIV-AIDS, understanding natural cell defenses to the HIV virus may identify new virus targets and strategies to block HIV in humans. Here, we will use state-of-the-art, high resolution, fluorescent microscopy to understand how the recently identified cell protein, APOBEC3G, blocks the HIV life cycle in human cells. We anticipate that APOBEC3G will stop HIV from invading the nucleus of human cells to defend against HIV, a strategy we can apply to new therapies.