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Phosphinophosphonates and Their Tris-pivaloyloxymethyl Prodrugs Reveal a Negatively Cooperative Butyrophilin Activation Mechanism
journal contribution
posted on 2017-02-20, 00:00 authored by 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. WiemerButyrophilin 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 (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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Keywords
prodrugNegatively Cooperative Butyrophilin Activation Mechanism Butyrophilin 3HMBPP-induced Hill coefficientsBTN 3Aactivates butyrophilin-responsive cells26 μ Mphosphinophosphonateallylic hydroxyl groupEC 50tris-POMTris-pivaloyloxymethyl Prodrugs RevealV γ9V T cellstarget cell lysisBTN 3A backbone0.041 μ Mleukemia cell lysis
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