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Development Of Novel Anticoagulants Inspired By Nature For Improved Ischaemic Stroke Therapy
Funder
National Health and Medical Research Council
Funding Amount
$716,396.00
Summary
Ischaemic stroke, caused by clots that obstruct blood flow to the brain, is the third most common cause of mortality and the leading cause of disability globally. Unfortunately, the only approved therapeutic option is ineffective for a significant proportion of stroke sufferers. This project will develop novel anticoagulants, inspired by molecules produced by blood feeding organisms, for use in more effective and safe ischaemic stroke therapy.
The West Nile Viral Protease, NS3: A Target For Antiviral Drug And Vaccine Design
Funder
National Health and Medical Research Council
Funding Amount
$230,500.00
Summary
The West Nile Virus (WNV) was first isolated from a woman in the West Nile region of Uganda in 1937. It is one of ~70 known flaviviruses (e.g. Dengue fever, Yellow fever, West Nile, Kunjun, Japanese encephalitis, St. Louis encephalitis, tick-borne encephalitis, Australian encephalitis and the related hepatitis C virus) which annually infect hundreds of millions of people worldwide, particularly in tropical and sub-tropical areas, and cause major public health problems. WNV is endemic in the Midd ....The West Nile Virus (WNV) was first isolated from a woman in the West Nile region of Uganda in 1937. It is one of ~70 known flaviviruses (e.g. Dengue fever, Yellow fever, West Nile, Kunjun, Japanese encephalitis, St. Louis encephalitis, tick-borne encephalitis, Australian encephalitis and the related hepatitis C virus) which annually infect hundreds of millions of people worldwide, particularly in tropical and sub-tropical areas, and cause major public health problems. WNV is endemic in the Middle East, parts of Africa and Europe, but recent epidemics in Israel (1998), Romania (1996), United States (1999), and UK (2003) have been characterized by severe symptoms , severe neurological pathology, and fatalities. In the USA alone there were 4,156 infections and 284 deaths in 2002, 9122 infections and 223 deaths in 2003, and this mosquito borne virus has quickly spread since 1999 through all USA states and into Canada and Mexico (http:--www.cdc.gov-ncidod-dvbid-westnile-index.htm). No treatments or vaccines are available. This project focuses on an enzyme, known as the West Nile Virus NS3 protease, that is essential for replication of the virus. By studying the enzyme in the laboratory we can design small molecules that can block its function and these have real potential as leads for development of drug treatments for people infected by this virus. A precedent is the success of inhibitors of HIV-1 protease that are the most effective treatment for humans with HIV-infections. Our studies will also be used to develop potential vaccines. The science involves experts on protease enzymes, drug design and development, virology including West Nile virology, and vaccine development. We expect to generate drug and vaccine candidates and new information for their development that is at the cutting edge of West Nile Virus research.Read moreRead less
Design And Delivery Of Peptide-based Anti-cancer Grb7 Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$603,126.00
Summary
The Grb7 protein is overproduced in many types of cancer cells and plays a role in cancer cell growth and spread. The current proposal builds upon the discovery of a peptide-based Grb7 inhibitor that has anti-cancer activity. This proposal is to prepare more potent inhibitor molecules that can efficiently reach the target cancer cells. Such molecules will be used for the study of Grb7 and for the development of a new Grb7-based anti-cancer drug therapy.
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
Exploring The Haemagglutinin-neuraminidase Of Human Parainfluenza Virus
Funder
National Health and Medical Research Council
Funding Amount
$731,268.00
Summary
Respiratory diseases, for example croup, in children are caused in the main by human parainfluenza viruses (hPIVs). No vaccines or specific antiviral therapy against hPIV infections exist. This project targets an essential protein in the virus’ lifecycle. This project will produce compounds that block the protein’s function and may provide drug candidates for development. Furthermore the role of human host cell-associated carbohydrates in parainfluenza infection will be better understood.
An Integrated Approach To Combat Antibiotic Resistance
Funder
National Health and Medical Research Council
Funding Amount
$389,120.00
Summary
The development of antibiotics such as penicillin was hailed as one of the great breakthroughs in medicine. However, an increasing number of pathogens have acquired resistance to these drugs. One of the most common resistance mechanisms employed by these pathogens is the use of metal dependent enzymes that promote the degradation of antibiotics. To date, no clinically useful inhibitors for these enzymes are available. In this project, we aim to develop such inhibitors as therapeutic drug leads.
Reversing Antibiotic Resistance With Efflux Pump Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$494,174.00
Summary
Antibiotic resistance in dangerous pathogens is one of the greatest threats to human health of the 21st century. The main cause of multidrug resistance is the presence of drug efflux pumps, which remove antibiotics from the bacterial cell thereby lowering the antibiotic concentration inside the cells to sub-toxic levels. We will use our expertise on these efflux pumps and on how to inhibit them to develop compounds that could reverse resistance and restore the activity of antibiotics.
Dengue virus is the most important mosquito-borne viral disease, with 2/3 of the world's population at risk. There is currently no treatment available for dengue. Our proposal aims to progress a safe and effective new treatment (4-HPR) against Dengue towards the clinic, generating all the required pharmacokinetic and pre-clinical animal data necessary to progress to a future clinical trial in humans. We will also investigate the use of 4-HPR as a dengue preventative.
Targeting Glycointeractions To Generate New Opportunities To Treat And Prevent Bacterial Infections.
Funder
National Health and Medical Research Council
Funding Amount
$774,540.00
Summary
Bacteria and bacterial toxins can interact with complex sugar structures on human cells called glycans. My research team has identified new and important glycan interactions used by bacteria that cause diseases ranging from pneumonia, meningitis and food borne infections to urinary tract and sexually transmitted diseases. Now that these interactions have been discovered, they can be exploited to create drugs and vaccines that may treat and prevent disease by blocking the glycan interactions.
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