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

Rebekah R Shippy; Xiaochen Lin; Sherry S Agabiti; Jin Li; Brendan M Zangari; Benjamin J Foust; Michael M Poe; Chia-Hung Christine Hsiao; Olga Vinogradova; David F Wiemer; Andrew J Wiemer

doi:10.1021/acs.jmedchem.6b00965

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

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

Rebekah R Shippy, Xiaochen Lin, Sherry S Agabiti, Jin Li, Brendan M Zangari, Benjamin J Foust, Michael M Poe, Chia-Hung Christine Hsiao, Olga Vinogradova, David F Wiemer, …

Journal of medicinal chemistry, Vol.60(6), pp.2373-2382

03/23/2017

DOI: 10.1021/acs.jmedchem.6b00965

PMCID: PMC5754923

PMID: 28218845

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https://www.ncbi.nlm.nih.gov/pmc/articles/5754923View

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Abstract

Butyrophilin 3A1 (BTN3A1) binds small phosphorus-containing molecules, which initiates transmembrane signaling and activates butyrophilin-responsive cells. We synthesized several phosphinophosphonates and their corresponding tris-pivaloyloxymethyl (tris-POM) 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 (EC = 26 μM). Cellular potency was enhanced >600-fold in the tris-POM prodrug (EC = 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.

Antigens, CD - metabolism

Butyrophilins - agonists

Butyrophilins - metabolism

Cell Line

Humans

K562 Cells

Lymphocyte Activation - drug effects

Molecular Docking Simulation

Organophosphonates - chemistry

Organophosphonates - pharmacology

Phosphines - chemistry

Phosphines - pharmacology

Prodrugs - chemistry

Prodrugs - pharmacology

T-Lymphocytes - drug effects

Details

Title: Subtitle: Phosphinophosphonates and Their Tris-pivaloyloxymethyl Prodrugs Reveal a Negatively Cooperative Butyrophilin Activation Mechanism
Creators: Rebekah R Shippy - Department of Chemistry, University of Iowa , Iowa City, Iowa 52242, United States
Xiaochen Lin - Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States
Sherry S Agabiti - Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States
Jin Li - Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States
Brendan M Zangari - Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States
Benjamin J Foust - Department of Chemistry, University of Iowa , Iowa City, Iowa 52242, United States
Michael M Poe - Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States
Chia-Hung Christine Hsiao - Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States
Olga Vinogradova - Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States
David F Wiemer - Department of Chemistry, University of Iowa , Iowa City, Iowa 52242, United States
Andrew J Wiemer - Institute for Systems Genomics, University of Connecticut , Storrs, Connecticut 06269, United States
Resource Type: Journal article
Publication Details: Journal of medicinal chemistry, Vol.60(6), pp.2373-2382
DOI: 10.1021/acs.jmedchem.6b00965
PMID: 28218845
PMCID: PMC5754923
NLM abbreviation: J Med Chem
ISSN: 0022-2623
eISSN: 1520-4804
Grant note: R01 CA186935 / NCI NIH HHS
Language: English
Date published: 03/23/2017
Academic Unit: Neuroscience and Pharmacology; Chemistry
Record Identifier: 9984216569102771

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