The two faces of LTA4H
LTA4H's pro- and anti-inflammatory effects call for inhibitor selectivity
Although the enzyme LTA4H has long been considered a driver of inflammatory diseases, companies have yet to create an inhibitor that succeeds in the clinic beyond Phase II. That could be due to a secondary, underappreciated, anti-inflammatory activity of the enzyme, according to researchers at Imperial College London, who are working on new compounds designed to selectively inhibit the target's inflammatory function.
LTA4H is most commonly known for generating the pro-inflammatory leukotriene LTB4, which it produces via its epoxide hydrolase activity, and which has been linked to inflammation in diseases such as cystic fibrosis (CF), colitis and psoriasis.
But LTA4H also has a peptidase activity that can break down small polypeptides such the neutrophil chemoattractant PGP, resulting in anti-inflammatory effects.
"It's a really unusual enzyme, in that it functions in a pro-inflammatory capacity to generate the neutrophil chemoattractant LTB4, and in an anti-inflammatory capacity to break down another neutrophil chemoattractant PGP," said Robert Snelgrove, a research lecturer at Imperial College.
In a 2010 study in Science, Snelgrove's lab first reported the anti-inflammatory side of LTA4H and its PGP-degrading activity.
Now, his team has