Journal article
Synthesis and Metabolism of BTN3A1 Ligands: Studies on Diene Modifications to the Phosphoantigen Scaffold
ACS medicinal chemistry letters, Vol.13(2), pp.164-170
02/10/2022
DOI: 10.1021/acsmedchemlett.1c00408
PMCID: PMC8842111
PMID: 35178171
Abstract
Phosphoantigens (pAgs) are small organophosphorus compounds such as (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) that trigger an immune response. These molecules bind to butyrophilin 3A1 (part of the HMBPP receptor) and activate Vγ9Vδ2 T cells. To explore the structure–activity relationships underlying this process, we evaluated a series of novel diene analogs of HMBPP. Here we report that prodrug forms of [(1E)-4-methylpenta-1,3-dien-1-yl] phosphonic acid that lack the allylic alcohol of HMBPP but instead contained a diene scaffold exhibit mid-nanomolar potency for the activation of Vγ9Vδ2 T cells. The compounds also trigger the production of T-cell interferon γ upon exposure to loaded K562 cells. Although both the allylic alcohol and the diene scaffold boost pAg activity, the combination of the two decreases the activity and results in glutathione conjugation. Together, these data show that the diene scaffold results in intermediate pAgs that may have implications for the mechanisms regulating the HMBPP receptor.
Details
- Title: Subtitle
- Synthesis and Metabolism of BTN3A1 Ligands: Studies on Diene Modifications to the Phosphoantigen Scaffold
- Creators
- Nyema M Harmon - Department of ChemistryMichael M Poe - Department of Pharmaceutical SciencesXueting Huang - Department of Pharmaceutical SciencesRohit Singh - Department of Pharmaceutical SciencesBenjamin J Foust - Department of ChemistryChia-Hung Christine Hsiao - Department of Pharmaceutical SciencesDavid F Wiemer - University of IowaAndrew J Wiemer - University of Connecticut
- Resource Type
- Journal article
- Publication Details
- ACS medicinal chemistry letters, Vol.13(2), pp.164-170
- Publisher
- American Chemical Society
- DOI
- 10.1021/acsmedchemlett.1c00408
- PMID
- 35178171
- PMCID
- PMC8842111
- ISSN
- 1948-5875
- eISSN
- 1948-5875
- Grant note
- DOI: 10.13039/100000054, name: National Cancer Institute, award: CA186935; DOI: 10.13039/100000060, name: National Institute of Allergy and Infectious Diseases, award: AI150869; DOI: 10.13039/100008893, name: University of Iowa, award: P200A150065; DOI: 10.13039/100000048, name: American Cancer Society, award: PF-18-119-01-LIB; DOI: 10.13039/100008038, name: Herman Frasch Foundation for Chemical Research, award: HF17; DOI: 10.13039/100001024, name: Roy J. Carver Charitable Trust
- Language
- English
- Date published
- 02/10/2022
- Academic Unit
- Neuroscience and Pharmacology; Chemistry
- Record Identifier
- 9984216680802771
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