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Sci Rep. 2017 Mar 17;7:44449. doi: 10.1038/srep44449.

The development of novel LTA4H modulators to selectively target LTB4 generation.

Author information

1
Computational Drug Design Consultant, Dulwich, London SE21 8LS, United Kingdom.
2
Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom.
3
Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom.
4
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
5
Birmingham V.A. Medical Center, Birmingham, AL 35294, USA.

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.

PMID:
28303931
PMCID:
PMC5355877
DOI:
10.1038/srep44449
[Indexed for MEDLINE]
Free PMC Article

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