University of Sussex
Browse
srep44449.pdf (1.39 MB)

The development of novel LTA4H modulators to selectively target LTB4 generation

Download (1.39 MB)
journal contribution
posted on 2023-06-09, 08:00 authored by Caroline M Low, Samia Akthar, Dhiren F Patel, Stephen Löser, Chi-Tung Wong Wong, Patricia L Jackson, J Edwin Blalock, Stephen Hare, Clare M Lloyd, Robert J Snelgrove
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Scientific Reports

ISSN

2045-2322

Publisher

Nature Publishing Group

Volume

7

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2017-09-21

First Open Access (FOA) Date

2017-09-21

First Compliant Deposit (FCD) Date

2017-09-21

Usage metrics

    University of Sussex (Publications)

    Categories

    No categories selected

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC