The development of novel LTA4H modulators to selectively target LTB4 generation
| Autor: | Low, CM, Akthar, S, Patel, D, Loeser, S, Wong, C, Jackson, P, Blalock, JE, Hare, S, Lloyd, C, Snelgrove, RJ |
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| Přispěvatelé: | Wellcome Trust, Asthma UK |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
ENZYME
AIRWAY INFLAMMATION Proline Neutrophils Amino Acid Motifs Anti-Inflammatory Agents Gene Expression Bone Marrow Cells EMPHYSEMA Crystallography X-Ray OBSTRUCTIVE PULMONARY-DISEASE Leukotriene B4 Article Protein Structure Secondary Substrate Specificity Mice NEUTROPHILIC INFLAMMATION LEUKOTRIENE A(4) HYDROLASE PROLINE-GLYCINE-PROLINE Animals Humans Protein Interaction Domains and Motifs Enzyme Inhibitors Epoxide Hydrolases Inflammation Mice Inbred BALB C Science & Technology Binding Sites Hydrolysis AMINOPEPTIDASE INHIBITOR Recombinant Proteins Multidisciplinary Sciences Molecular Docking Simulation DISCOVERY beta-Alanine Science & Technology - Other Topics Female Oligopeptides Protein Binding |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep44449 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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