1 research outputs found
Phosphinophosphonates and Their Tris-pivaloyloxymethyl Prodrugs Reveal a Negatively Cooperative Butyrophilin Activation Mechanism
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 (<i>E</i>)-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<sub>50</sub> = 26 μM). Cellular potency was enhanced >600-fold in the
tris-POM
prodrug (EC<sub>50</sub> = 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