Objective

The pro-inflammatory lipid mediator leukotriene B4 (LTB4) is implicated in the pathologies of an array of diseases and thus represents an attractive therapeutic target. The enzyme leukotriene A4 hydrolase (LTA4H) catalyses the distal step in LTB4 synthesis and hence inhibitors of this enzyme have been actively pursued. Despite potent LTA4H inhibitors entering clinical trials, all have failed to show efficacy. We recently identified a secondary anti-inflammatory role for LTA4H in degrading the tripeptide Pro-Gly-Pro (PGP). PGP is a bioactive fragment of extracellular matrix collagen with pro-inflammatory and pro-remodelling activity. LTA4H is therefore an unusual enzyme with opposing pro- and anti-inflammatory activities and we rationalized that the failure of conventional LTA4H inhibitors may be that they inadvertently prevented PGP degradation. Here I discuss our current understanding of PGP biology and the importance of the dual roles of LTA4H in defining disease pathophysiology. Accordingly, we have developed novel compounds that inhibit LTB4 generation whilst leaving PGP degradation unperturbed. These novel compounds could represent a safer and superior class of LTA4H inhibitors for translation into the clinic.