Elastase is a serine protease that has been implicated in a number of inflammatory conditions including rheumatoid arthritis and cystic fibrosis. These conditions are thought to result from an increased amount of active elastase in the body, caused by insufficient inhibition by endogenous inhibitors. Elastase has the ability to degrade many tissue components and this excessive tissue damage causes the onset of a variety of conditions. This knowledge has led to an increased interest in the production of elastase inhibitors with the hope of developing an inhibitor, which can be of therapeutic use <i>in vivo. </i>As a result we have synthesised a series of novel β-lactams since β-lactam compounds are known to be mechanism-based inhibitors of serine proteases. Electrospray ionisation mass spectrometry (ESI-MS) identified a novel mode of inhibition, for β-lactams which possess a hydroxyl group present at the C3 position, resulting in the formation of an acyl-enzyme intermediate which was found to be extremely stable. Enzyme kinetic studies demonstrated that the β-lactams had k<sub>ass</sub> values ranging from 1000 - 10,000 M<sup>-1</sup> s<sup>-1</sup>. The novel β-lactams were also assayed for activity against trypsin. ESI-MS confirmed that they were also inhibitors or trypsin but enzyme kinetic studies revealed that they were more active towards elastase. Therefore the novel β-lactams were found to be stable, potent and specific inhibitors of elastase that may of therapeutic use in the treatment of many inflammatory conditions.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:652900 |
| Date | January 2002 |
| Creators | Jackson, Lynn |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/15094 |
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