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
Functional Analysis Of The Roles Of The Serine Protease Kallikrein 7 And Its Variant Isoform In Serous Ovarian Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$509,017.00
Summary
Ovarian cancer is the leading cause of death from gynaecological cancers with 1,200 women in Australia diagnosed with the disease in 2004, and 852 patients dying of ovarian cancer. The mortality rate has improved little over the last two decades with one of the major reasons being that ovarian cancer is often diagnosed at a late stage when cancer cells have spread into the abdomen or metastasised to other sites. The kallikrein family of serine proteases or enzymes is emerging as very useful diag ....Ovarian cancer is the leading cause of death from gynaecological cancers with 1,200 women in Australia diagnosed with the disease in 2004, and 852 patients dying of ovarian cancer. The mortality rate has improved little over the last two decades with one of the major reasons being that ovarian cancer is often diagnosed at a late stage when cancer cells have spread into the abdomen or metastasised to other sites. The kallikrein family of serine proteases or enzymes is emerging as very useful diagnostic or prognostic biomarkers for ovarian cancer as they often have higher levels in ovarian cancer tissue compared to the normal ovary. One of these enzymes is kallikrein 7, which is also involved in shedding of skin cells. Because of its involvement in skin, we hypothesise it may be playing a similar role in ovarian cancer and helping the cancer cells to detach from the ovary so they are free to move around the body to other sites. There are two different forms of kallikrein 7, a long form and a shorter form which is lacking a part that is crucial to enzymatic activity. While low levels of the short form have been found in normal ovary, very high levels of both forms were seen in ovarian cancer, especially the serous subtype which is the most common and most aggressive form of ovarian cancer. The aim of this project is to determine the function(s) of both forms of kallikrein 7 in ovarian cancer and to identify other molecules-proteins they are involved with. These findings will tell us if kallikrein 7 is involved in the spreading of ovarian cancer cells or metastasis and will lead to a better understanding of the development and progression of ovarian cancer. The finding from this study may also lead to better therapeutic approaches (ie blocking the action of Kallikrein 7), and-or markers to monitor ovarian cancer progression.Read moreRead less
Control Of Mast Cell Tryptase Function In Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$302,627.00
Summary
Allergic disorders such as anaphylaxis, eczema, hay fever and asthma affect about 25% of the developed world. Australia has one of the highest asthma prevalence in the world, costing Australians about a billion dollars a year. One of the central players in allergies is the mast cell enzyme, ?-tryptase. We have discovered a new mechanism of control of this enzyme. This research will aid the development of specific and potent inhibitors of ?-tryptase for the treatment of allergic disorders.
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.
Flaviviral Proteases As Viable Targets For Antiinfective Drugs
Funder
National Health and Medical Research Council
Funding Amount
$620,716.00
Summary
Viruses hijack the machinery and nutrients of cells they infect in order to reproduce. We will study viral enzymes (proteases) essential for virus replication, use fluorescent probes to learn where the viral enzymes hide and act in infected cells, track the passage of drugs aimed at these enzymes, design drugs to block their actions and stop virus replication, and test antiviral activity against Dengue, West Nile, Japanese Encephalitis and Yellow Fever viruses which infect millions of people.