Opportunities and challenges in development of phosphoantigens as Vγ9Vδ2 T cell agonists

Wiemer, David F.; Wiemer, Andrew J.

doi:10.1016/j.bcp.2014.03.009

Cited by 27 publications

(44 citation statements)

References 85 publications

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“…Additionally, the most potent naturally occurring BTN3A1 agonist, HMBPP, contains a diphosphate that limits both its stability and its access to the intracellular BTN3A1 binding site. 20 We hypothesized herein that tris-POM phosphinophosphonate prodrugs (e.g. 4 ), which closely mimic the structure of HMBPP, would produce a strong cellular response due to the increased stability of the -C-P-C-P linkage versus the -O-P-O-P substructure found in HMBPP, and the improved cell permeability of the prodrug form.…”

Section: Discussionmentioning

confidence: 99%

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Phosphinophosphonates and Their Tris-pivaloyloxymethyl Prodrugs Reveal a Negatively Cooperative Butyrophilin Activation Mechanism

et al. 2017

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Butyrophilin 3A1 (BTN3A1) binds small phosphorous-containing molecules, which initiates transmembrane signaling and activates butyrophilin-responsive cells. We synthesized several phosphinophosphonates and their corresponding tris-pivaloyloxymethyl prodrugs and examined their effects on BTN3A1. An analog of (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) bound to BTN3A1 with intermediate affinity, which was enthalpy-driven. Docking studies revealed binding to the basic surface pocket and interactions between the allylic hydroxyl group and the BTN3A1 backbone. The phosphinophosphonate stimulated proliferation of Vγ9Vδ2 T cells with moderate activity (EC50 = 26 µM). Cellular potency was enhanced >600-fold in the tris-POM prodrug (EC50 = 0.041 µM). The novel prodrug also induced T cell mediated leukemia cell lysis. Analysis of dose response data reveals HMBPP-induced Hill coefficients of 0.69 for target cell lysis and 0.68 in interferon secretion. Together, tris-POM prodrugs enhance the cellular activity of phosphinophosphonates, reveal structure-activity relationships of butyrophilin ligands, and support a negatively cooperative model of cellular butyrophilin activation.

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Section: Discussionmentioning

confidence: 99%

“…When combined with the potential for tight control of active BTN3A1 through multi-ligand binding and negative cooperativity, this model is one way to account for both the exquisite sensitivity of Vγ9Vδ2 T cells to HMBPP and the tremendous range of phosphoantigen cellular potencies that covers over 7 orders of magnitude. 20 …”

Section: Discussionmentioning

confidence: 99%

Phosphinophosphonates and Their Tris-pivaloyloxymethyl Prodrugs Reveal a Negatively Cooperative Butyrophilin Activation Mechanism

et al. 2017

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“…Vγ9Vδ2 T cells detect the small molecule (phosphoantigen) HMBPP [4]. As HMBPP is not produced by mammals, this sensitivity is indicative of a role for Vγ9Vδ2 T cells in pathogen elimination [5].…”

Section: Introductionmentioning

confidence: 99%

HMBPP Analog Prodrugs Bypass Energy-Dependent Uptake To Promote Efficient BTN3A1-Mediated Malignant Cell Lysis by Vγ9Vδ2 T Lymphocyte Effectors

Kilcollins

Hsiao

et al. 2016

The Journal of Immunology

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Vγ9Vδ2 T effectors lyse cells in response to phosphorus-containing small molecules, providing primates a unique route to remove infected or malignant cells. Yet, the triggering mechanisms remain ill-defined. We examined lysis mediated by human Vγ9Vδ2 T effectors in response to the naturally-occurring (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) or a synthetic cell-permeable prodrug, bis (pivaloyloxymethyl) (E)-4-hydroxy-3-methyl-but-2-enyl phosphonate (POM2-C-HMBP). CD27+/CD45RA− Th1-like effector cells killed K562 target cells though a mechanism that could be enhanced by either compound or TCR antibody and blocked by Src inhibition or BTN3A1 disruption. Pre-treatment at 4°C decreased HMBPP-induced lysis but did not reduce lysis induced by POM2-C-HMBP. Together, our results show that internalization of HMBPP into target cells is required for BTN3A1-dependent lysis by Vγ9Vδ2 T effectors. The enhanced activity of the prodrug analog is due to its ability to bypass the pathways required for entry of HMBPP. These findings support an inside-out model of T cell triggering driven by small-molecule induction of BTN3A1.

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“…[11] Therefore, development of HMBPP analogues which can contribute to understanding its immunostimulatory mechanism is warranted. [12] …”

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confidence: 99%

Evaluation of a 7‐Methoxycoumarin‐3‐carboxylic Acid Ester Derivative as a Fluorescent, Cell‐Cleavable, Phosphonate Protecting Group

et al. 2015

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Cell-cleavable protecting groups often enhance cellular delivery of species that are charged at physiological pH. Although several phosphonate protecting groups have achieved clinical success, it remains difficult to use these prodrugs in live cells to clarify biological mechanisms. Here we present a strategy that uses a 7-methoxycoumarin-3-carboxylic acid ester as a fluorescent protecting group. This strategy is applied to synthesis of an HMBPP analogue to assess cellular uptake and human Vγ9Vδ2 T cell activation. The fluorescent ester displays low cell toxicity (IC50 >100 μM) and strong T cell activation (EC50 = 0.018 μM) relative to the unprotected anion (EC50 = 23 μM). The coumarin-derived analogue allows no-wash analysis of biological deprotection, which reveals rapid internalization of the prodrug. These results demonstrate that fluorescent groups can be applied both as functional drug delivery tools and useful biological probes of drug uptake.

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Opportunities and challenges in development of phosphoantigens as Vγ9Vδ2 T cell agonists

Cited by 27 publications

References 85 publications

Phosphinophosphonates and Their Tris-pivaloyloxymethyl Prodrugs Reveal a Negatively Cooperative Butyrophilin Activation Mechanism

Phosphinophosphonates and Their Tris-pivaloyloxymethyl Prodrugs Reveal a Negatively Cooperative Butyrophilin Activation Mechanism

HMBPP Analog Prodrugs Bypass Energy-Dependent Uptake To Promote Efficient BTN3A1-Mediated Malignant Cell Lysis by Vγ9Vδ2 T Lymphocyte Effectors

Evaluation of a 7‐Methoxycoumarin‐3‐carboxylic Acid Ester Derivative as a Fluorescent, Cell‐Cleavable, Phosphonate Protecting Group

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