ArticleScientific reports2017
Feasibility and physiological relevance of designing highly potent aminopeptidase-sparing leukotriene A4 hydrolase inhibitors.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 33 citations in OpenAlex.
- Leukotriene A4 hydrolase inhibition improves age-related cognitive decline via modulation of synaptic function.Science advances · 2023Article
- Polyunsaturated Fatty Acids: Conversion to Lipid Mediators, Roles in Inflammatory Diseases and Dietary Sources.International journal of molecular sciences · 2023Review
- Modulation of the 5-Lipoxygenase Pathway by Chalcogen-Containing Inhibitors of Leukotriene AInternational journal of molecular sciences · 2023Article
- Substrate-dependent modulation of the leukotriene AScientific reports · 2022Article
- An inhibitor of leukotriene-AProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Current Status of the Use of Multifunctional Enzymes as Anti-Cancer Drug Targets.Pharmaceutics · 2021Review
- Untangling the web of 5-lipoxygenase-derived products from a molecular and structural perspective: The battle between pro- and anti-inflammatory lipid mediators.Biochemical pharmacology · 2021Review
- Identification of Human Leukotriene A4 Hydrolase Inhibitors Using Structure-Based Pharmacophore Modeling and Molecular Docking.Molecules (Basel, Switzerland) · 2020Article
- Design of Dual Inhibitors of Soluble Epoxide Hydrolase and LTAACS medicinal chemistry letters · 2020Article
- IRAP Inhibitors: M1-Aminopeptidase Family Inspiration.Frontiers in pharmacology · 2020Review
- Label-free target identification reveals oxidative DNA damage as the mechanism of a selective cytotoxic agent.Chemical science · 2019Article
- Leukotriene biosynthetic enzymes as therapeutic targets.The Journal of clinical investigation · 2018Review
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22 authors at 1 institution in 1 country.
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Abstract
Leukotriene A4 Hydrolase (LTA4H) is a bifunctional zinc metalloenzyme that comprises both epoxide hydrolase and aminopeptidase activity, exerted by two overlapping catalytic sites. The epoxide hydrolase function of the enzyme catalyzes the biosynthesis of the pro-inflammatory lipid mediator leukotriene (LT) B4. Recent literature suggests that the aminopeptidase function of LTA4H is responsible for degradation of the tripeptide Pro-Gly-Pro (PGP) for which neutrophil chemotactic activity has been postulated. It has been speculated that the design of epoxide hydrolase selective LTA4H inhibitors that spare the aminopeptidase pocket may therefore lead to more efficacious anti-inflammatory drugs. In this study, we conducted a high throughput screen (HTS) for LTA4H inhibitors and attempted to rationally design compounds that would spare the PGP degrading function. While we were able to identify compounds with preference for the epoxide hydrolase function, absolute selectivity was not achievable for highly potent compounds. In order to assess the relevance of designing such aminopeptidase-sparing LTA4H inhibitors, we studied the role of PGP in inducing inflammation in different settings in wild type and LTA4H deficient (LTA4H KO) animals but could not confirm its chemotactic potential. Attempting to design highly potent epoxide hydrolase selective LTA4H inhibitors, therefore seems to be neither feasible nor relevant.
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