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
Agonists And Antagonists Of The Human Complement C3a Receptor
Funder
National Health and Medical Research Council
Funding Amount
$473,250.00
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. One of the most important complement proteins is known as C3a. It is called an anaphyla ....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. One of the most important complement proteins is known as C3a. It is called an anaphylatoxin and is thought to be a pivotal component of the complement system synthesized by the human body early on in the development of inflammatory and immune diseases. New compounds that could stimulate or block the activity of C3a are expected : (a) To lead us to a better understanding of how C3a binds to its receptors on immune cells and its role 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. It is not yet possible to examine detailed structures of the receptors on cells that interact with complement proteins. However it is possible to determine and analyse three dimensional structures of small molecules that can bind to human immune cells, and mimic or block effects of human C3a on cells, rat tissues, and in whole rats. We will identify and improve such small molecules by optimising their binding to immune cells, by tailoring them to selectively block or mimic just the effects of C3a, and by making them pharmacologically stable for administration (preferably by mouth) to rats (and humans). We will then test them in rats for potential future development into a completely new type of anti-inflammatory drug, one that treats inflammatory disease processes rather than just the symptoms like most current antiinflammatory drugs.Read moreRead less
Development Of An In Vivo Pharmacokinetic-pharmacodynamic Model For Evaluation Of Antimalarial Drug Therapy Combinations
Funder
National Health and Medical Research Council
Funding Amount
$120,604.00
Summary
The World Health Organization currently estimates that there are 300-500 million cases of malaria annually, with 1.5-2.7 million deaths. These are staggering data, given that almost 20 antimalarial drugs are now in regular clinical use. Multi-drug resistance is present in most tropical countries where malaria is endemic and there has been a rapid escalation in cases of malaria in developed countries over recent decades (imported by travellers). Clearly, there is a need to ensure that current and ....The World Health Organization currently estimates that there are 300-500 million cases of malaria annually, with 1.5-2.7 million deaths. These are staggering data, given that almost 20 antimalarial drugs are now in regular clinical use. Multi-drug resistance is present in most tropical countries where malaria is endemic and there has been a rapid escalation in cases of malaria in developed countries over recent decades (imported by travellers). Clearly, there is a need to ensure that current and new treatment and prevention strategies are rational and effective. This project is based on the premise that improvements can be made in the in vitro testing process of antimalarial drugs. The experiments will be conducted using mice and a form of malaria that is specific to mice but closely resembles human malaria. In the first stage, the relationship between the amount of a new antimalarial drug (dihydroartemisinin) in the body and the effectiveness of the dose will be tested. These experiments will be repeated using conventional antimalarial drugs such as mefloquine. Information from these studies will subsequently be used to evaluate combinations of antimalarials. The results will be used as the basis of extensive, collaborative clinical studies in South-East Asia that are beyond the scope of this project. The methods used for this research will be important for future testing of new antimalarial drugs or combinations of drugs for the treatment and prophylaxis of malaria.Read moreRead less
This project will examine new ways in which the major effector cells of allergic inflammation and asthma are regulated by novel S100 protein mediators. We find two natural proteins of the innate immune system, present in cells in the lungs of patients with acute asthma. These have apparently opposing activates: one, S100A12, activates mast cells to release mediators that trigger asthma attack. We will characterise how this proteins is regulated in eosinophils, key cells in asthma. Because mast c ....This project will examine new ways in which the major effector cells of allergic inflammation and asthma are regulated by novel S100 protein mediators. We find two natural proteins of the innate immune system, present in cells in the lungs of patients with acute asthma. These have apparently opposing activates: one, S100A12, activates mast cells to release mediators that trigger asthma attack. We will characterise how this proteins is regulated in eosinophils, key cells in asthma. Because mast cells reside in almost all body tissues and are also important mediators of host responses to allergy, infection and in chronic inflammation such as rheumatoid arthritis and psoriasis, our studies may indicate novel and unexpected ways in which they are activated. A second S100 protein (S100A8) is an efficient scavenger of oxidants that can cause damage to the lung. We find both S100A12 and S100A8 that has been modified by oxidants, in sputum from pateints with asthma. In addition to its anti-oxidant effects, S100A8 can downregulate production of some of the inflammatory mediators that promote allergy and asthma. This is an important finding that will help us understand how drugs used in treatment, such as steroids, are acting. We will generate a mouse expressing this protein in its lungs and determine how this affects normal lungs and the course of asthma. If, as we expect, asthma is reduced, we will have found a novel new pathway that is important in the resolution of asthma. Results from this project will provide new knowledge concerning mechanisms of regulation in allergy and asthma and may lead to the design of novel strategies to regulate the process. Results will have broader ramifications applicable to other chronc inflammatory where these proteins are expressed. We have new reagents that could also assist in the diagnosis of these conditions and may be useful for monitoring treatment.Read moreRead less