Vacuolar H+-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments.
Vacuolar H+-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments.
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DOI：
10.21037/biotarget.2017.12.01
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发表时间：
2017-12-01
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通讯作者：
Holliday, L Shannon
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作者：
Holliday, L Shannon
极性H+-ATP酶（V-ATP酶）是一种多亚基酶，在真核细胞中通过酸化溶酶体、晚期内体、高尔基体和其他膜结合区室发挥管家作用。除此之外，V-ATP酶在与骨质疏松症和癌症等疾病相关的某些细胞类型中具有特殊功能。二十多年来，一直在努力确定开发对参与疾病进展的V-ATP酶具有选择性的抑制剂的策略，但迄今为止尚未产生已转化为临床的治疗剂。最近的基础科学研究已经确定了V-ATP酶在营养和能量传感以及肾素/血管紧张素信号传导中的意想不到的作用，这为考虑V-ATP酶作为治疗靶点提供了额外的激励。本文简要综述了近年来利用V-ATP酶抑制剂作为药物的研究进展。主要的焦点是最近的“合理”的努力，以确定小分子抑制剂的V-ATP酶，选择性地表达在破骨细胞和癌细胞。依诺沙星和双依诺沙星是从这些努力中出现的两种分子。这些分子阻断V-ATP酶和微丝之间的结合相互作用，该结合相互作用发生在破骨细胞中，但不是大多数其他细胞类型，这涉及V-ATP酶在骨吸收中的专门功能。依诺沙星和双依诺沙星已被证明可用于治疗骨疾病和癌症的动物模型，并显示出不同的治疗效果，也许比目前的药物更好。这些结果提供了证据表明，以V-ATP酶亚群为靶点的药物可能在临床上是有用的。
Vacuolar H+-ATPases (V-ATPases) are multi-subunit enzymes that play housekeeping roles in eukaryotic cells by acidifying lysosomes, late endosomes, Golgi, and other membrane-bounded compartments. Beyond that, V-ATPases have specialized functions in certain cell types linked to diseases including osteoporosis and cancer. Efforts to identify strategies to develop inhibitors selective for V-ATPases that are involved in disease progression have been ongoing for more than two decades, but so far have not yielded a therapeutic agent that has been translated to the clinic. Recent basic science studies have identified unexpected roles for V-ATPases in nutrient and energy sensing, and renin/angiotensin signaling, which offer additional incentives for considering V-ATPases as therapeutic targets. This article briefly reviews efforts to utilize inhibitors of V-ATPases as drugs. Primary focus is on recent "rational" efforts to identify small molecule inhibitors of the V-ATPases that are selectively expressed in osteoclasts and cancer cells. Enoxacin and bis-enoxacin are two molecules that emerged from these efforts. These molecules block a binding interaction between V-ATPases and microfilaments that occurs in osteoclasts, but not most other cell types, which relates to the specialized function of V-ATPases in bone resorption. Enoxacin and bis-enoxacin have proven useful in the treatment of bone diseases and cancer in animal models and display therapeutic effects that are different, and perhaps better, than current drugs. These results provide evidence that agents targeting subsets of V-ATPases may prove useful in the clinic.