Phosphinophosphonates and Their Tris-pivaloyloxymethyl Prodrugs Reveal a Negatively Cooperative Butyrophilin Activation Mechanism.
Rebekah R ShippyXiaochen LinSherry S AgabitiJin LiBrendan M ZangariBenjamin J FoustMichael M PoeChia-Hung Christine HsiaoOlga VinogradovaDavid F WiemerAndrew J WiemerPublished in: Journal of medicinal chemistry (2017)
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 (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.
Keyphrases
- single cell
- high glucose
- cancer therapy
- diabetic rats
- induced apoptosis
- cell therapy
- genome wide
- oxidative stress
- cell cycle arrest
- bone marrow
- endothelial cells
- electronic health record
- drug induced
- molecular dynamics
- molecular dynamics simulations
- cell proliferation
- dendritic cells
- machine learning
- gene expression
- stem cells
- cell death
- big data
- artificial intelligence