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The development of novel LTA4H modulators to selectively target LTB4 generation

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Title: The development of novel LTA4H modulators to selectively target LTB4 generation
Authors: Low, CM
Akthar, S
Patel, D
Loeser, S
Wong, C
Jackson, P
Blalock, JE
Hare, S
Lloyd, C
Snelgrove, RJ
Item Type: Journal Article
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.
Issue Date: 17-Mar-2017
Date of Acceptance: 8-Feb-2017
URI: http://hdl.handle.net/10044/1/44416
DOI: https://dx.doi.org/10.1038/srep44449
ISSN: 2045-2322
Publisher: Nature Publishing Group
Journal / Book Title: Scientific Reports
Volume: 7
Copyright Statement: © The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Sponsor/Funder: Wellcome Trust
Asthma UK
Funder's Grant Number: 095707/Z/11/Z
AUK-IG-2014-286
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
LEUKOTRIENE A(4) HYDROLASE
OBSTRUCTIVE PULMONARY-DISEASE
PROLINE-GLYCINE-PROLINE
NEUTROPHILIC INFLAMMATION
AIRWAY INFLAMMATION
INHIBITOR
ENZYME
AMINOPEPTIDASE
DISCOVERY
EMPHYSEMA
Publication Status: Published
Article Number: 44449
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine
Faculty of Natural Sciences



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