Design and Development Of Small Molecules To Regulate Protease Activated Receptor Type 2

Funded Activity Summary

A new class of proteins have been discovered on the surface of cells. These are activated by enzymes known as proteases and are therefore called Protease Activated Receptors (PARs). PARs appear to be very important 'sensors' of proteases outside cells, becoming activated in response to very low concentrations of proteases. This suggest that proteases may exert some of their biological effects through these receptors, which are now implicated in a growing number of diseases (e.g. thrombosis, cardiovascular disorders, asthma, inflammatory bowel disease, Crohn's disease, pancreatitis, stomach and colon cancer, arthritis, and there may also be a role in wound healing). We are working towards dissecting the roles for one of these receptors (PAR2) in disease by developing small molecules for selective binding to this receptor. We will particularly distinguish between compounds that can activate (agonists) or deactivate (antagonists) the receptor. These experiments will involve computer-assisted compound design, structural comparisons between small molecules with activity and those without, and cellular studies designed to measure affinity, activation and deactivation of PAR2. The outcome will be a series of small molecules that bind tightly to the PAR2 receptor and have a well defined function (antagonist, agonist, partial agonist). While the above studies are in progress some peptides that are known to activate this receptor will be examined in rodent models of human disease (airways inflammation, pancreatitis, stomach and colon cancer, arthritis). Studies like this have been very revealing for us in the past (Nature 1999, 398, 156-160 A protective role for protease-activated receptors in the airways). Then the designed and developed compounds will also be examined for signs of therapeutic potential. The work will provide a better understanding of how this receptor works and a clearer picture of the role of this receptor in human disease.

Funded Activity Details

Start Date: 01-01-2003

End Date: 01-01-2005

Funding Scheme: NHMRC Project Grants

Funding Amount: $439,500.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Enzymes

ANZSRC Socio-Economic Objective (SEO)

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Other Keywords

Antagonists | Inflammation | Peptidomimetics | Pharmacology | Protease Activated Receptors | arthritis | asthma | cancer | pancreatitis

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