Vacuolar ATPase as a drug discovery target
Vacuolar ATPase as a drug discovery target
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DOI：
10.1358/dnp.2006.19.3.977442
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发表时间：
2006-04-01
影响因子：
--
通讯作者：
Niikura, Kazuaki
中科院分区：
文献类型：
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作者：
Niikura, Kazuaki
极性ATP酶（V-ATP酶）不仅存在于特化细胞的质膜中，而且存在于普遍存在的细胞内酸性区室中，其对于生理细胞功能是必需的。因此，尽管V-ATP酶在几种疾病的病因学上是重要的，但似乎它们可能不是良好的分子靶点。事实上，巴弗洛霉素A（1），一种有效的和特异性的V-ATP酶抑制剂，当给药于动物时会产生严重的急性毒性反应。另一方面，V-ATP酶α 3亚基的破坏不是胚胎致死性的，但敲除小鼠仅表现出骨硬化症，由于骨吸收的损失。此外，最近的研究已经证明，具有抑制选择性的新型V-ATP酶抑制剂可以全身给予动物，并且在溶骨性疾病模型中对骨丢失非常有效。因此，关于V-ATP酶抑制剂的治疗有用性的关键问题是它们在抑制中的选择性。(c)2006年，《科学》杂志。All rights reserved.
Vacuolar ATPases (V-ATPases) are present not only in the plasma membranes of specialized cells but also in ubiquitous intracellular acidic compartments, which are essential for physiological cellular function. Consequently, although V-ATPases are important etiologically in several diseases, it seems that they might not be good molecular targets. In fact, bafilomycin A(1), a potent and specific inhibitor of V-ATPase, exerts severe and acute toxic reaction when administered to animals. On the other hand, disruption of subunit a3 of V-ATPase is not embryonic lethal, but knockout mice merely exhibit osteopetrosis due to loss of osteoclastic bone resorption. In addition, recent studies have demonstrated that novel V-ATPase inhibitors, which have inhibition selectivity, can be systemically administered to animals and are highly efficacious against bone loss in lytic bone disease models. Therefore, the key issue regarding the therapeutic usefulness of V-ATPase inhibitors is their selectivity in the inhibition. (c) 2006 Prous Science. All rights reserved.