The Bioactivity And Binding Partners Of Irukandji And Box Jellyfish Venom
Funder
National Health and Medical Research Council
Funding Amount
$596,950.00
Summary
Venom from the Box Jellyfish and Irukandji jellyfish are considered the most leathal known to science yet precious little is known on the nature of these secretions or how they harm humans. This study aims to fully characterise bioactive proteins in jellyfish venom and attempt to block their activity using regulatory-approved and experimental drugs.
Biochemical And Molecular Dissection Of The Mechanisms Controlling Ribosome Biogenesis By The PI3K/AKT/mTOR/MYC Network
Funder
National Health and Medical Research Council
Funding Amount
$545,180.00
Summary
Ribosome synthesis and function are critical for normal cell growth and division and hence this process is exquisitely regulated. Conversely, de-regulated cell growth can lead to cancer. We have identified new roles for the AKT and SGK families of kinases in controlling this process. This proposal aims to establish the mechanisms by which these enzymes control ribosome synthesis to better understand growth control and to provide insight for targeting these pathways in growth driven cancers.
Developing Synergisers Of The Antimalarial Drug, Chloroquine, For The Treatment Of Chloroquine-resistant P. Falciparum.
Funder
National Health and Medical Research Council
Funding Amount
$243,000.00
Summary
Malaria is a debilitating parasitic disease that is responsible for the deaths of about two million children each year. As drugs, such as chloroquine, become increasingly useless due to the development of parasite resistance, there is an urgent need to understand the mode of action of and the molecular basis of resistance to existing antimalarials and to design affordable treatments that can replace chloroquine. It is known that some compounds, that have only poor antimalarial activity themselve ....Malaria is a debilitating parasitic disease that is responsible for the deaths of about two million children each year. As drugs, such as chloroquine, become increasingly useless due to the development of parasite resistance, there is an urgent need to understand the mode of action of and the molecular basis of resistance to existing antimalarials and to design affordable treatments that can replace chloroquine. It is known that some compounds, that have only poor antimalarial activity themselves, can synergise the action of chloroquine. This may involve the inhibition of the activity of proteins that directly or indirectly extrude chloroquine from its site of action in the parasite's digestive apparatus. Unfortunately, thechloroquine synergisers examined to date have been too toxic to be useful in vivo. In preliminary studies we have identified some compounds that would be suitable for use in malaria patients, including a widely used antimalarial drug, primaquine, that can synergise the activity of chloroquine against chloroquine-resistant parasites. We will attempt to understand the molecular basis of this interaction. This will allow us to define optimal combinations of chloroquine and a resistance-reversing quinoline for use treating malaria. This could extend the clinical life of this important antimalarial drug. The information obtained may also help to design novel antimalarial drugs.Read moreRead less
Inhibitors Of West Nile Virus Protease As Antiviral Drugs
Funder
National Health and Medical Research Council
Funding Amount
$590,740.00
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 people i ....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 people in the Middle East, parts of Africa and Europe, but recent epidemics in Israel (1998), Romania (1996), United States (1999), and UK (2003), that have been traced to migratory birds, were 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 a viral 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 block its function and these are potential leads for developing drug treatments for people infected, not only by this virus but potentially also other flaviviruses. A precedent is the success of inhibitors of HIV-1 protease that are the most effective treatment for humans with HIV-infections, and other viral proteases are now becoming recognized as viable antiviral targets for pharmaceutical development. The project involves experts on small molecule protease inhibitor design and development, proteases, and virology including West Nile virology. We expect to generate new information at the cutting edge of West Nile Virus and flavivirus research and promising new antiviral drug candidates.Read moreRead less
Development Of A Protein Tyrosine Kinase Inhibitor For Modification Of GAG Chains And Prevention Of Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$389,778.00
Summary
The major health issue in Australia is vascular and cardiovascular disease resulting from obesity and diabetes. Whilst prevention strategies based on lifestyle changes are preferable, treating cardiovascular risk factors with the latest drugs has been shown to produce significant benefits. There is however a large group of patients who still acquire cardiovascular disease in spite of drug therapy. New therapies are required and these will most likely target blood vessels directly. We have identi ....The major health issue in Australia is vascular and cardiovascular disease resulting from obesity and diabetes. Whilst prevention strategies based on lifestyle changes are preferable, treating cardiovascular risk factors with the latest drugs has been shown to produce significant benefits. There is however a large group of patients who still acquire cardiovascular disease in spite of drug therapy. New therapies are required and these will most likely target blood vessels directly. We have identified a biochemical mechanism that represents a prime target for vascular wall directed therapy and we aim to exploit the therapeutic potential of this pathway by developing a drug to prevent atherosclerosis. A group of large molecules which have recently received increasing attention are the proteoglycans, combined protein-sugar molecules which are heavily coated with negatively charged groups. The binding and retention of lipids in the wall of the blood vessel is the main cause of atherosclerosis. Specifically, the length of the sugar (GAG) chains on the proteoglycans determines the binding of the lipids. We have discovered a new class of inhibitors which directly target proteoglycan synthesis in the vessel wall and greatly reduce the interaction between proteoglycans and lipids. We wish to demonstrate the efficacy of our compound in an animal model with the aim to produce a marked reduction in the rate and extent of development of atherosclerosis. This would lay the foundation for the compound to be taken into human safety trials and subsequently develop an agent for the prevention of atherosclerosis and a thus a reduction in cardiovascular disease.Read moreRead less
Mechanisms Of Control Of Cell Growth And Proliferation By The AKT Kinase Family
Funder
National Health and Medical Research Council
Funding Amount
$568,452.00
Summary
Ribosome synthesis and function is critical for normal cell growth and division and hence this process is exquisitely regulated. Conversely, de-regulated cell growth can lead to cancer. We have identified new roles for the AKT and SGK families of kinases in controlling this process. This proposal aims to establish the mechanisms by which these enzymes control ribosome synthesis to better understand growth control and to provide insight for targeting these pathways in growth driven cancers.
Regulation Of Cardiac Hypertrophy A At The Level Of Ribosome Biogenesis
Funder
National Health and Medical Research Council
Funding Amount
$634,587.00
Summary
A major feature of cardiac hypertrophy (enlarged heart) is accelerated cell growth and protein synthesis. This results from increased synthesis of ribosomes (the protein synthetic machinery). This study will examine a factor termed UBF whose activity is critical for the regulation of ribosome synthesis. Understanding the mechanisms controlling UBF function will provide new avenues in which to develop therapeutics to combat hypertrophic heart disease.
Targeting The Mannose Activation Pathway In Leishmania - Novel Drug Targets And Vaccines.
Funder
National Health and Medical Research Council
Funding Amount
$338,661.00
Summary
Leishmaniasis is a parasitic disease ranging in severity from skin lesions to fatal systemic infection. It is a serious public health problem throughout many regions of the world. Co-infection with HIV has emerged as a serious problem in Africa, South America and southern Europe. Recently, leishmaniasis has been identified in East Timor and in kangaroos in Australia. Treatment of leishmaniasis is based on chemotherapy, but currently used drugs are expensive, have high toxicity and unwanted side ....Leishmaniasis is a parasitic disease ranging in severity from skin lesions to fatal systemic infection. It is a serious public health problem throughout many regions of the world. Co-infection with HIV has emerged as a serious problem in Africa, South America and southern Europe. Recently, leishmaniasis has been identified in East Timor and in kangaroos in Australia. Treatment of leishmaniasis is based on chemotherapy, but currently used drugs are expensive, have high toxicity and unwanted side effects. They have also been compromised by the emergence of resistance in the parasite. Leishmania synthesises a range of surface molecules, which are needed for virulence and parasite survival in the host. The biosynthesis process of these molecules requires activated mannose. We have identified two novel parasite genes encoding for enzymes, which are essential for the biosynthesis of surface virulence factors. When either of these genes is deleted the parasite can no longer cause disease. This suggests that drugs targeting the two enzymes will be able to control the infection. We will produce crystals of these enzymes and solve their 3D structure using state of the art technology to screen libraries of synthetic chemicals to find candidate inhibitors of enzyme activity. When these compounds are identified we will use computer modelling to design compounds based on these inhibitors and crystal structure, which will lead to a new generation of anti-Leishmania drugs. We will also determine whether the avirulent parasites can be used as an attenuated vaccine. Recovery from infection leads to a solid immunity and protection from subsequent infection indicating that vaccination is feasible, but despite of a huge amount of research there is no antileishmanial vaccine currently available. This study will lead to potential novel antileishmanial drugs and vaccines. It will also provide fundametal new knowledge of the structure of enzymes critical for parasite virulence.Read moreRead less
Fungal Phospholipases: A Novel Drug Discovery Platform
Funder
National Health and Medical Research Council
Funding Amount
$588,679.00
Summary
Invasive fungal infections are a serious and escalating health issue. They cause severe disease with a high death rate and are very costly to the health system. This is especially the case in immunocompromised patients, such as those with blood malignancies, organ transplant recipients and AIDS. The number of currently available drugs for the treatment of fungal infections is limited and they are, in general, either not very effective or toxic. The development of fungal strains resistant to thes ....Invasive fungal infections are a serious and escalating health issue. They cause severe disease with a high death rate and are very costly to the health system. This is especially the case in immunocompromised patients, such as those with blood malignancies, organ transplant recipients and AIDS. The number of currently available drugs for the treatment of fungal infections is limited and they are, in general, either not very effective or toxic. The development of fungal strains resistant to these drugs is also becoming problematic. There is an urgent need to discover and develop new drugs effective against fungal infections through identifying new targets in the fungal cell and-or targets that prevent the spread of infection in the human host. We were the first to describe an enzyme, phospholipase B (PLB1), which is secreted by the medically important fungus, Cryptococcus neoformans, and is important in invasion of human tissue by the fungus. It is also important in remodelling of membranes in the fungal cell. This enzyme is sufficiently different from human phospholipases to be a good target for antifungal drugs. In this project, we aim to synthesise and test molecules which should inhibit the activity of PLB 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 used to kill the fungal cells, especially if administered together with currently used therapies. The design and development of new antifungal drugs with a novel mode of action represents a major advance in the treatment of fungal disease, and a saving of some A$60000 per affected patient (estimated from a recent US study).Read moreRead less