So far, attempts to design drugs that block the enzyme LTA4 hydrolase, a key player in the body's inflammatory response, have shown only moderate effectiveness in clinical trials. But researchers at Sweden's Karolinska Institutet think they've discovered why previous efforts at targeting this enzyme have failed and have produced a new molecule that may prove more successful.
The enzyme LTA4 hydrolase has been linked to inflammatory conditions like COPD, the vascular disease arteriosclerosis and chronic eczema. It has two main functions, which are seemingly opposite: one pathway elicits an inflammatory response by producing the molecule LTB4, while a second pathway contributes to healing by disabling the tripeptide Pro-Gly-Pro, which is formed during degradation of connective tissue and contributes to inflammation.
Previous experimental drugs meant to treat inflammatory conditions that block the LTA4 hydrolase have knocked out both of these functions. Researchers at the Karolinska Institutet have instead designed a molecule that inhibits LTA4 hydrolase from producing LTB4, which contributes to inflammation and the inactivation of Pro-Gly-Pro, while leaving Pro-Gly-Pro inactivated. This means that LTA4 hydrolase is able to act as an anti-inflammatory in both pathways.
Using x-ray crystallography to study LTA4 hydrolase, the Karolinska scientists found that LTB4 formation takes place at different parts of the enzyme's active site, the part of the enzyme used for biochemical communication.
The researchers hope that their findings, published March 3 in the Early Edition of the Proceedings of the National Academy of Sciences, could be used as a basis for drug design to treat various inflammatory diseases.
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- see the study abstract