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
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 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
Post-transcriptional Regulation Of Plasminogen Activator Inhibitor 2 Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$508,838.00
Summary
Plasminogen activator inhibitor type 2 (PAI-2) is a protease inhibitor that has intracellular and extracellular functions. The PAI-2 gene is highly regulated at the level of PAI-2 mRNA stability. We have identified regions within the PAI-2 transcript essential for this regulation and a number of novel proteins that engage these regions. This project is aimed at understanding how these and other proteins control PAI-2 expression at the mRNA level.
C3/C5 Convertase Inhibitors As A New Class Of Anti-Inflammatory Drugs
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
Many serious inflammatory diseases, such as arthritis, septic shock, lung shock, heart disease, atherosclerosis, multiple sclerosis, are poorly controlled with currently available drugs. There is a great deal of evidence that naturally occuring Complement proteins in human blood are involved in exacerbating these and many other human diseases, yet there are no good drugs available to counteract their effects. Three complement proteins known as C3a, C5a and MAC (membrane attack complex) are thoug ....Many serious inflammatory diseases, such as arthritis, septic shock, lung shock, heart disease, atherosclerosis, multiple sclerosis, are poorly controlled with currently available drugs. There is a great deal of evidence that naturally occuring Complement proteins in human blood are involved in exacerbating these and many other human diseases, yet there are no good drugs available to counteract their effects. Three complement proteins known as C3a, C5a and MAC (membrane attack complex) are thought to be particularly pivotal components of the complement system synthesized by the human body early in the development of inflammatory and immune diseases. New compounds that could block the formation of human C3a, C5a and MAC are expected : (a) To lead us to a better understanding of how these proteins act on immune cells and of their respective roles in the immune response to infection and injury, and (b) To enable the rapid development of an entirely new class of drugs for treating autoimmune and inflammatory diseases. No Complement-based drugs are yet available in man. In other NHMRC funded work we have developed compounds (antagonists) that selectively block the actions of human C3a or C5a, and shown that they are effective antiinflammatory agents in rat models of a number of inflammatory diseases. In this project we will design and develop small molecules that block the enzymes (C3-C5 convertases) that make C3a, C5a and other complement proteins including MAC. We expect that such inhibitors will be even more effective antinflammatory drugs because they will block formation of multiple complement proteins that each have proinflammatory activity. We will demonstrate selective effects of the new compounds on components of complement, and test them in rat models of inflammatory diseases. We expect C3-C5 convertase inhibitors to be a completely new type of anti-inflammatory drug, treating disease processes rather than symptoms like current drugs.Read moreRead less
Complement Inhibitors For Treatment Of Chronic Inflammatory Diseases
Funder
National Health and Medical Research Council
Funding Amount
$623,606.00
Summary
We aim to provide new therapeutic approaches to gum disease, which not only causes tooth loss, but also contributes to other diseases, such as cardiovascular disease and diabetes. We will find new methods to inhibit a system in our own bodies that contributes to inflammation and gum disease and test the effects of these methods of inhibition in disease models. In this way, we hope to lessen the burden of gum disease on the Australian population.