An Investigation Of Vibrio Cholerae Sialidase As A Target For Drug Discovery
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
The prevalence of the disease Cholera still causes significant human mortality, in particular in underdevloped countries. The process that enables the cholera toxin to cause signficant damage is now partly understood. This research project will provide a range of chemical entities (probes) that have the potential of intervening in this process . These probes will be the basis for a drug discovery programme that targets toxin binding. Through molecular modelling based on protein structural inform ....The prevalence of the disease Cholera still causes significant human mortality, in particular in underdevloped countries. The process that enables the cholera toxin to cause signficant damage is now partly understood. This research project will provide a range of chemical entities (probes) that have the potential of intervening in this process . These probes will be the basis for a drug discovery programme that targets toxin binding. Through molecular modelling based on protein structural information, drug candidate synthesis and evaluation of these compounds in relevant test tube (in vitro) assays it is envisaged that a number of candidate compounds will be then further optimised for eventual pre-clinical investigation. The technology to be used in this project is comparable to that we have used in the discovery of the recently approved influenza drug, Relenza .Read moreRead less
Development Of Novel Hybrid Antibiotics For The Treatment Of Hospital And Community Acquired Drug Resistant Gram-Negative And Gram-Postitive Bacterial Infections
Funder
National Health and Medical Research Council
Funding Amount
$715,076.00
Summary
Drug resistant bacteria now pose a serious and growing threat to human health. Many bacteria have developed new resistance mechanisms such that most common antibiotics no longer can protect patients from serious, life-threatening infection. We will modify two existing antibiotics, colistin and carbapenem (a penicillin), to convert it into a more powerful antibiotic that targets resistant bacteria.
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
Molecular Characterization Of Dengue Virus Fusion And Antiviral Inhibitors.
Funder
National Health and Medical Research Council
Funding Amount
$573,557.00
Summary
Dengue viruses are transmitted by mosquitoes and cause major epidemics in more than 100 countries around the world, including Australia. Infection with dengue viruses cause severe and sometimes fatal disease. This proposal focuses on the way dengue virus enters cells and the development of drugs that will prevent virus entry. We have already identified compounds that inhibit the entry process of dengue into cells and this project will significantly build on these early findings.
The Mechanism Of Action Of New 5-nitroimidazole Drugs Which Are Effective Against Metronidazole-resistant Giardia
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
We have discovered new 5-nitroimidazole drugs which can overcome giardial resistance to metronidazole, the most prescribed 5-nitroimidazole drug to treat giardiasis. We will focus on defining mechanisms of action of these new 5-nitroimidazole drugs in the anaerobic gut protozoan parasite Giardia. Using biochemical techniques, we will determine whether our potent new drugs are activated more efficiently by the same mechanisms as metronidazole or by novel enzyme pathways in the parasite.
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
Inhibition Of Siderophore Biosynthesis For Tuberculosis Drug Discovery
Funder
National Health and Medical Research Council
Funding Amount
$424,262.00
Summary
Tuberculosis (TB) is responsible for over 2 million deaths globally every year. Despite this alarming statistic, no new TB drugs have reached the market in 40 years. This is despite the emergence of strains of Mycobacterium tuberculosis (the causative agent of TB) that are resistant to currently prescribed drugs. This project aims to discover TB drug leads with a unique mode of action. This will be achieved by preparing compounds that prevent the bacterium from acquiring iron from the host.
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.
The Design And Synthesis Of Sialyltransferase Inhibitors As Anti-metastatic Agents
Funder
National Health and Medical Research Council
Funding Amount
$273,629.00
Summary
The prevalence of cancer and, in particular, cancer that spreads throughout the body has risen over the past twenty years in the human population and causes significant human mortality. A correlation between some of a cancerous cell's surface componentary and the ability of this cell to spread throughout the body has been established. This research project will provide a range of chemical entities (probes) that will intervene in this spreading process (metastasis). These probes will be the basis ....The prevalence of cancer and, in particular, cancer that spreads throughout the body has risen over the past twenty years in the human population and causes significant human mortality. A correlation between some of a cancerous cell's surface componentary and the ability of this cell to spread throughout the body has been established. This research project will provide a range of chemical entities (probes) that will intervene in this spreading process (metastasis). These probes will be the basis for a drug discovery programme that targets a particular aspect of the spreading process. Through molecular modelling, drug candidate synthesis and evaluation of these compounds in relevant test tube (in vitro) assays it is envisaged that a number of candidate compounds will then be evaluated in an animal model (in vivo assay). The technology to be used in this project is comparable to that which we used in the discovery of the recently approved influenza drug, Relenza?.Read moreRead less