Membrane Permeant Analogs for Independent Cellular Introduction of the Terpene Precursors Isopentenyl‐ and Dimethylallyl‐Pyrophosphate
Membrane Permeant Analogs for Independent Cellular Introduction of the Terpene Precursors Isopentenyl‐ and Dimethylallyl‐Pyrophosphate
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用于独立细胞引入萜烯前体异戊烯基和二甲基烯丙基焦磷酸盐的膜渗透类似物
DOI：
10.1002/cbic.202200512
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发表时间：
2023
期刊：
影响因子：
3.2
通讯作者：
Baccile, Joshua A.
中科院分区：
文献类型：
--
作者：
Rossi, Francis M.;McBee, Dillon P.;Trybala, Thomas N.;Hulsey, Zackary N.;Gonzalez Curbelo, Camila;Mazur, William;Baccile, Joshua A.
异戊烯焦磷酸 (IPP) 和二甲基烯丙基焦磷酸 (DMAPP) 是所有萜烯的中心五碳前体。尽管它们很重要，但将 IPP 和 DMAPP 外源性、独立地递送至细胞是不可能的，因为带负电荷的焦磷酸盐使这些分子不具有膜渗透性。在此，我们展示了一种简单的方法来规避这一挑战，通过用两种自焚酯（SIE）对β-磷酸酯进行酯化，中和带负电荷的焦磷酸盐，产生IPP和DMAPP的膜渗透类似物。细胞掺入后，一般酯酶活性启动 SIE 裂解，导致 IPP 和 DMAPP 无痕释放以供代谢利用。添加合成的 IPP 和 DMAPP 前体类似物可以挽救同时用 HMG-CoA 还原酶抑制剂匹伐他汀治疗的胶质母细胞瘤 (U-87MG) 癌细胞的细胞生长，否则匹伐他汀会通过阻断 IPP 和 DMAPP 的产生来抑制细胞生长。这项工作展示了前药策略整合代谢中间体的新应用，并有望在未来探究 IPP 和 DMAPP 的不同生物学作用。
Isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) are the central five‐carbon precursors to all terpenes. Despite their significance, exogenous, independent delivery of IPP and DMAPP to cells is impossible as the negatively charged pyrophosphate makes these molecules membrane impermeant. Herein, we demonstrate a facile method to circumvent this challenge through esterification of the β‐phosphate with two self‐immolative esters (SIEs) that neutralize the negatively charged pyrophosphate to yield membrane‐permeant analogs of IPP and DMAPP. Following cellular incorporation, general esterase activity initiates cleavage of the SIEs, resulting in traceless release of IPP and DMAPP for metabolic utilization. Addition of the synthesized IPP and DMAPP precursor analogs rescued cell growth of glioblastoma (U‐87MG) cancer cells concurrently treated with the HMG‐CoA reductase inhibitor pitavastatin, which otherwise abrogates cell growth via blocking production of IPP and DMAPP. This work demonstrates a new application of a prodrug strategy to incorporate a metabolic intermediate and promises to enable future interrogation of the distinct biological roles of IPP and DMAPP.