Abstract
The pro-inflammatory 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 neutrophil chemoattractant Pro-Gly-Pro (PGP) and rationalized that the failure of conventional LTA4H inhibitors may be that they inadvertently prevented PGP degradation. We demonstrate that these inhibitors do indeed fail to discriminate between the dual activities of LTA4H, and enable PGP accumulation in mice. Accordingly, we have developed novel compounds that potently 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.
Highlights
We identified a secondary anti-inflammatory activity for Leukotriene A4 hydrolase (LTA4H) whereby it functions as an aminopeptidases to degrade the tripeptide Pro-Gly-Pro (PGP)[9]
It is apparent that the two activities of LTA4H occur via distinct but overlapping active sites, both located in a deep L-shaped cleft
LTA4H inhibitors developed by pharmaceutical companies to alleviate leukotriene B4 (LTB4)-mediated pathologies have demonstrated clear target engagement, but failed to show efficacy in the clinic
Summary
We identified a secondary anti-inflammatory activity for LTA4H whereby it functions as an aminopeptidases to degrade the tripeptide Pro-Gly-Pro (PGP)[9]. Significant quantities of PGP are found in patients with chronic neutrophilic lung diseases such as chronic obstructive pulmonary disease (COPD), Cystic Fibrosis (CF) and bronchiolitis obliterans syndrome (BOS), peaking with exacerbation of disease and inversely correlating with lung function[10,11,14,15,16,17]. It seems that the LTA4H-PGP degradation pathway is perturbed in these chronic diseases to enable PGP to accumulate and drive inflammation[9,15,18]. Haeggstrom and colleagues have suggested that it is feasible to selectively inhibit the epoxide hydrolase activity whilst leaving the aminopeptidase activity unperturbed, demonstrating that the molecule 4-(4-benzylphenyl) thiazol-2 amine (ARM1) could inhibit LTB4 generation without affecting PGP degradation[37]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
