title: Synthesis of a phosphoantigen prodrug that potently activates Vγ9Vδ2 T-lymphocytes.
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.
authors: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors: Chia-Hung Christine
authors: CH
authors: Hsiao
authors: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors: Xiaochen
authors: X
authors: Lin
authors: Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA; Department of Chemistry, Western Wyoming Community College, Rock Springs, WY 82901, USA.
authors: Rocky J
authors: RJ
authors: Barney
authors: Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA.
authors: Rebekah R
authors: RR
authors: Shippy
authors: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors: Jin
authors: J
authors: Li
authors: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors: Olga
authors: O
authors: Vinogradova
authors: Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA; Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA.
authors: David F
authors: DF
authors: Wiemer
authors: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA. Electronic address: andrew.wiemer@uconn.edu.
authors: Andrew J
authors: AJ
authors: Wiemer
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D015394:Molecular Structure; D010755:Organophosphates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*
chemical_list: D010755:Organophosphates; D011355:Prodrugs