Synthesis and Evaluation of Mevalonate Diphosphate Analogs as Butyrophilin 3A3 Ligands

Abstract Butyrophilin 3A3 (BTN3A3) senses mevalonate-derived phosphoantigens (pAgs), but its ligand chemistry remains unexplored. We synthesized phosphonate analogs of mevalonate diphosphate (MPP) and evaluated their stimulation of γ9δ2 T cells. Several compounds induced interferon γ production from human effector γ9δ2 T cells, although none potently stimulated naïve-γ9δ2 T cell proliferation. Compound 17 was the most active pAg; it outperformed MPP and preferentially acted in BTN3A3-expressing cells. Compound 17 resisted the lovastatin-mediated pathway blockade and, importantly, synergized with POM2-C-HMBP, a BTN3A1 agonist. These findings identify 17 as a BTN3A3-biased pAg and support chemically tuning mevalonate-derived scaffolds to modulate γ9δ2 T cell responses.