Synthesis and Metabolism of BTN3A1 Ligands: Studies on Diene Modifications to the Phosphoantigen Scaffold,ACS Medicinal Chemistry Letters

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Synthesis and Metabolism of BTN3A1 Ligands: Studies on Diene Modifications to the Phosphoantigen Scaffold
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2022-01-27 , DOI: 10.1021/acsmedchemlett.1c00408
Nyema M Harmon ₁ , Michael M Poe ₂ , Xueting Huang ₂ , Rohit Singh ₂ , Benjamin J Foust ₁ , Chia-Hung Christine Hsiao ₂ , David F Wiemer _{1,

3} , Andrew J Wiemer _{2,

4}

Affiliation

Phosphoantigens (pAgs) are small organophosphorus compounds such as (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) that trigger an immune response. These molecules bind to butyrophilin 3A1 (part of the HMBPP receptor) and activate Vγ9Vδ2 T cells. To explore the structure–activity relationships underlying this process, we evaluated a series of novel diene analogs of HMBPP. Here we report that prodrug forms of [(1E)-4-methylpenta-1,3-dien-1-yl] phosphonic acid that lack the allylic alcohol of HMBPP but instead contained a diene scaffold exhibit mid-nanomolar potency for the activation of Vγ9Vδ2 T cells. The compounds also trigger the production of T-cell interferon γ upon exposure to loaded K562 cells. Although both the allylic alcohol and the diene scaffold boost pAg activity, the combination of the two decreases the activity and results in glutathione conjugation. Together, these data show that the diene scaffold results in intermediate pAgs that may have implications for the mechanisms regulating the HMBPP receptor.

中文翻译：

BTN3A1 配体的合成与代谢：二烯修饰磷酸抗原支架的研究

磷酸抗原 (pAg) 是触发免疫反应的小型有机磷化合物，例如 ( E )-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP)。这些分子与嗜乳蛋白 3A1（HMBPP 受体的一部分）结合并激活 Vγ9Vδ2 T 细胞。为了探索该过程背后的构效关系，我们评估了一系列 HMBPP 的新型二烯类似物。在这里，我们报告 [(1 E)-4-methylpenta-1,3-dien-1-yl] 膦酸缺乏 HMBPP 的烯丙醇，而是含有二烯支架，对 Vγ9Vδ2 T 细胞的激活表现出中纳摩尔级的效力。这些化合物还会在暴露于负载的 K562 细胞时触发 T 细胞干扰素 γ 的产生。尽管烯丙醇和二烯支架都能增强 pAg 活性，但两者的结合会降低活性并导致谷胱甘肽结合。总之，这些数据表明二烯支架产生中间 pAg，这可能对调节 HMBPP 受体的机制有影响。

更新日期：2022-02-10

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