From the Gla domain to a novel small-molecule detector of apoptosis
From the Gla domain to a novel small-molecule detector of apoptosis
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DOI：
10.1038/cr.2009.17
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发表时间：
2009-05-01
期刊：
影响因子：
44.1
通讯作者：
Ziv, Ilan
中科院分区：
文献类型：
--
作者：
Cohen, Avi;Shirvan, Anat;Ziv, Ilan
细胞凋亡在许多医学疾病的病因学或发病机制中发挥着关键作用，因此，针对凋亡细胞的靶向可能会大大促进患者护理。在寻找新型低分子量细胞凋亡探针的过程中，我们重点研究了不常见的氨基酸-羧基谷氨酸 (Gla)，它在凝血因子与带负电的磷脂表面的结合中发挥着至关重要的作用。基于 Gla 的烷基丙二酸基序，我们开发并现已推出 ML-10（2-(5-氟戊基)-2-甲基-丙二酸，MW=206 Da），它是新型细胞凋亡小分子检测器家族的典型成员。 ML-10被发现在凋亡细胞中选择性摄取和积累，同时被活细胞或坏死细胞排除。 ML-10 摄取与 caspase 激活、Annexin-V 结合和线粒体膜电位破坏等细胞凋亡标志相关。发现丙二酸部分对于细胞凋亡检测中的 ML-10 功能至关重要。 ML-10 对细胞早期凋亡过程中独特的复杂特征做出反应，包括不可逆的膜电位损失、细胞膜和细胞质的永久酸化以及膜完整性的保存。因此，ML-10 是迄今为止已知的最紧凑的细胞凋亡探针。由于含有氟原子，ML-10 适合用 (18)F 同位素进行放射性标记，未来有望用于细胞凋亡的临床正电子发射断层扫描成像。
Apoptosis plays a pivotal role in the etiology or pathogenesis of numerous medical disorders, and thus, targeting of apoptotic cells may substantially advance patient care. In our quest for novel low-molecular-weight probes for apoptosis, we focused on the uncommon amino acid.-carboxyglutamic acid (Gla), which plays a vital role in the binding of clotting factors to negatively charged phospholipid surfaces. Based on the alkyl-malonic acid motif of Gla, we have developed and now present ML-10 (2-(5-fluoro-pentyl)-2-methyl-malonic acid, MW=206 Da), the prototypical member of a novel family of small-molecule detectors of apoptosis. ML-10 was found to perform selective uptake and accumulation in apoptotic cells, while being excluded from either viable or necrotic cells. ML-10 uptake correlates with the apoptotic hallmarks of caspase activation, Annexin-V binding and disruption of mitochondrial membrane potential. The malonate moiety was found to be crucial for ML-10 function in apoptosis detection. ML-10 responds to a unique complex of features of the cell in early apoptosis, comprising irreversible loss of membrane potential, permanent acidification of cell membrane and cytoplasm, and preservation of membrane integrity. ML-10 is therefore the most compact apoptosis probe known to date. Due to its fluorine atom, ML-10 is amenable to radio-labeling with the (18)F isotope, towards its potential future use for clinical positron emission tomography imaging of apoptosis.