srep44449.pdf (1.39 MB)
The development of novel LTA4H modulators to selectively target LTB4 generation
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 SnelgroveThe 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 ReportsISSN
2045-2322Publisher
Nature Publishing GroupExternal DOI
Volume
7Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2017-09-21First Open Access (FOA) Date
2017-09-21First Compliant Deposit (FCD) Date
2017-09-21Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC