Journal article
Phosphonamidate Prodrugs of a Butyrophilin Ligand Display Plasma Stability and Potent Vγ9 Vδ2 T Cell Stimulation
Journal of medicinal chemistry, Vol.61(19), pp.8658-8669
2018
DOI: 10.1021/acs.jmedchem.8b00655
PMID: 30199251
Abstract
Small organophosphorus compounds stimulate Vγ9 Vδ2 T cells if they serve as ligands of butyrophilin 3A1. Because the most potent natural ligand is ( E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), which is the last intermediate in bacterial biosynthesis of isoprenoids that is not found in mammalian metabolism, activation of these T cells represents an important component of the immune response to bacterial infections. To identify butyrophilin ligands that may have greater plasma stability, and clinical potential, we have prepared a set of aryl phosphonamidate derivatives (9a-i) of the natural ligand. Testing of these new compounds in assays of T cell response has revealed that this strategy can provide compounds with high potency for expansion of Vγ9 Vδ2 T cells (9f, EC50 = 340 pM) and interferon γ production in response to loaded K562 cells (9e, EC50 = 62 nM). Importantly, all compounds of this class display extended plasma stability ( t1/2 > 24 h). These findings increase our understanding of metabolism of butyrophilin ligands and the structure-activity relationships of phosphonamidate prodrugs.
Details
- Title: Subtitle
- Phosphonamidate Prodrugs of a Butyrophilin Ligand Display Plasma Stability and Potent Vγ9 Vδ2 T Cell Stimulation
- Creators
- Nicholas A LentiniBenjamin J FoustChia Hung Christine HsiaoAndrew J WiemerDavid F Wiemer
- Resource Type
- Journal article
- Publication Details
- Journal of medicinal chemistry, Vol.61(19), pp.8658-8669
- DOI
- 10.1021/acs.jmedchem.8b00655
- PMID
- 30199251
- NLM abbreviation
- J Med Chem
- ISSN
- 1520-4804
- eISSN
- 1520-4804
- Publisher
- American Chemical Society (ACS)
- Grant note
- DOI: 10.13039/100000054, name: National Cancer Institute, award: R01CA186935; DOI: 10.13039/100008038, name: Herman Frasch Foundation for Chemical Research, award: HF17; DOI: 10.13039/100001024, name: Roy J. Carver Charitable Trust, award: 01-224
- Language
- English
- Date published
- 2018
- Academic Unit
- Neuroscience and Pharmacology; Chemistry
- Record Identifier
- 9983985714102771
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