Developing Anti-Inflammatory Drugs Based On Inhibition Of A Human Enzyme
Funder
National Health and Medical Research Council
Funding Amount
$160,000.00
Summary
Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachid ....Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachidonate, PAF, prostaglandins, leukotrienes, etc. there is a consensus that blockade of phospholipid metabolism would represent a major advance on NSAIDs as antiinflammatory agents. No sPLA2-IIa inhibitor is available yet in man. We aim to create an attractive data package showing proof of concept for a potent new type of antiinflammatory drug. This data will give us an improved negotiating position in our commercialisation of a new drug with potential multi-billion dollar markets as diverse as arthritis, asthma, reperfusion injury, organ transplantation and many other currently intractable human ailmentsRead moreRead less
The Mechanism Of Action Of Secreted Phospholipase A2 And Its Inhibition In Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$554,400.00
Summary
Secretory phospholipase A2 (sPLA2) is an important mediator of inflammation and is clinically associated with the onset and severity of several immune-mediated diseases including arthritis, asthma, atherosclerosis, psoriasis and recently prostate cancer. These are complex diseases which are poorly understood. We have shown that sPLA2 can by itself and in combination with inflammatory cytokines modulate signalling pathways in cells derived from the joints of patients with arthritis to upregulate ....Secretory phospholipase A2 (sPLA2) is an important mediator of inflammation and is clinically associated with the onset and severity of several immune-mediated diseases including arthritis, asthma, atherosclerosis, psoriasis and recently prostate cancer. These are complex diseases which are poorly understood. We have shown that sPLA2 can by itself and in combination with inflammatory cytokines modulate signalling pathways in cells derived from the joints of patients with arthritis to upregulate inflammatory molecules. How this happens is completely unknown. We plan to work out how this enzyme does this. We have also developed small cyclic peptide inhibitors of sPLA2 which potently block the function of the enzyme in these cells. We plan to determine how this happens and if these inhibitors are effective at blocking inflammation and arthritis. The proposal may identify new mechanisms by which secreted factors upregulate inflammation in human cells and may lead to the discovery of new ways to intervene to block these pathways.Read moreRead less
Identification Of Novel Targets For Treatment Of Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$486,873.00
Summary
Hearts respond to stimulation by activation of cell surface receptors. We have found that two very closely related receptors have opposing effects on the heart; one is beneficial and the other promotes disease. The planned studies will investigate exactly what explains this difference. This will identify critical factors that protect or damage the heart and is expected to provide suitable targets for drug development.