Synthesis of a phosphoantigen prodrug that potently activates Vγ9Vδ2 T-lymphocytes

Chia-Hung Christine Hsiao; Xiaochen Lin; Rocky J Barney; Rebekah R Shippy; Jin Li; Olga Vinogradova; David F Wiemer; Andrew J Wiemer

doi:10.1016/j.chembiol.2014.06.006

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Synthesis of a phosphoantigen prodrug that potently activates Vγ9Vδ2 T-lymphocytes

Journal article

Open access

Synthesis of a phosphoantigen prodrug that potently activates Vγ9Vδ2 T-lymphocytes

Chia-Hung Christine Hsiao, Xiaochen Lin, Rocky J Barney, Rebekah R Shippy, Jin Li, Olga Vinogradova, David F Wiemer and Andrew J Wiemer

Chemistry & biology, Vol.21(8), pp.945-954

08/14/2014

DOI: 10.1016/j.chembiol.2014.06.006

PMID: 25065532

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Abstract

Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. However, the mechanisms by which phosphoantigens stimulate Vγ9Vδ2 T cells are unclear. Here, we synthesized phosphoantigen prodrugs and used them to demonstrate that intracellular delivery of phosphoantigens is required for their activity. The pivaloyloxymethyl prodrug is the most potent phosphoantigen described to date, with stronger stimulation of Vγ9Vδ2 T cells from human peripheral blood and greater ability to induce lysis of Daudi lymphoma cells relative to the previously most potent compound, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). We demonstrate high binding affinity between phosphoantigens and the intracellular region of butyrophilin 3A1 (BTN3A1), localized to the PRY/SPRY (B30.2) domain, but also affecting the membrane proximal region. Our findings promote a phosphoantigen prodrug approach for cancer immunotherapy and unravel fundamental aspects of the mechanisms of Vγ9Vδ2 T cell activation.

T-Lymphocyte Subsets - immunology

T-Lymphocyte Subsets - cytology

Humans

Cells, Cultured

Prodrugs - chemistry

Structure-Activity Relationship

Dose-Response Relationship, Drug

Organophosphates - pharmacology

Lymphocyte Activation - drug effects

T-Lymphocyte Subsets - drug effects

T-Lymphocyte Subsets - metabolism

Organophosphates - chemical synthesis

Prodrugs - chemical synthesis

Organophosphates - chemistry

Molecular Structure

Prodrugs - pharmacology

Details

Title: Subtitle: Synthesis of a phosphoantigen prodrug that potently activates Vγ9Vδ2 T-lymphocytes
Creators: Chia-Hung Christine Hsiao - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA
Xiaochen Lin - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA
Rocky J Barney - Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA; Department of Chemistry, Western Wyoming Community College, Rock Springs, WY 82901, USA
Rebekah R Shippy - Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA
Jin Li - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA
Olga Vinogradova - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA
David F Wiemer - Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA; Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA
Andrew J Wiemer - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA. Electronic address: andrew.wiemer@uconn.edu
Resource Type: Journal article
Publication Details: Chemistry & biology, Vol.21(8), pp.945-954
DOI: 10.1016/j.chembiol.2014.06.006
PMID: 25065532
NLM abbreviation: Chem Biol
ISSN: 1074-5521
eISSN: 1879-1301
Publisher: United States
Language: English
Date published: 08/14/2014
Academic Unit: Neuroscience and Pharmacology; Chemistry
Record Identifier: 9983985840802771

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