沃克帕唑（TAK-438）对胃H⁺，K⁺ -ATP酶的结合选择性。
The binding selectivity of vonoprazan (TAK-438) to the gastric H+, K+ -ATPase.
作者信息
Scott D R, Munson K B, Marcus E A, Lambrecht N W G, Sachs G
机构信息
Department of Physiology, DGSOM at UCLA, Los Angeles, CA, USA.
VA GLAHS, Los Angeles, CA, USA.
出版信息
Aliment Pharmacol Ther. 2015 Dec;42(11-12):1315-26. doi: 10.1111/apt.13414. Epub 2015 Sep 30.
BACKGROUND
The gastric H(+) ,K(+) -ATPase is the preferred target for acid suppression. Until recently, the only drugs that effectively inhibited this ATPase were the proton pump inhibitors (PPIs). PPIs are acid-activated prodrugs that require acid protection. Once acid-activated, PPIs bind to cysteines of the ATPase, resulting in covalent, long-lasting inhibition. The short plasma half-life of PPIs and continual de novo synthesis of the H(+) ,K(+) -ATPase result in difficulty controlling night-time acid secretion. A new alternative to PPIs is the pyrrolo-pyridine, vonoprazan (TAK-438), a potassium-competitive acid blocker (PCAB) that does not require acid protection. In contrast to other PCABs, vonoprazan has a long duration of action, resulting in 24-h control of acid secretion, a high pKa of 9.37 and high affinity (Ki = 3.0 ηmol/L).
AIM
To determine binding selectivity of vonoprazan for the gastric H(+) ,K(+) -ATPase and to explain its slow dissociation.
METHODS
Gastric gland and parietal cell binding of vonoprazan was determined radiometrically. Molecular modelling explained the slow dissociation of vonoprazan from the H(+) ,K(+) -ATPase.
RESULTS
Vonoprazan binds selectively to the parietal cell, independent of acid secretion. Vonoprazan binds in a luminal vestibule between the surfaces of membrane helices 4, 5 and 6. Exit of the drug to the lumen is hindered by asp137 and asn138 in the loop between TM1 and TM2, which presents an electrostatic barrier to movement of the sulfonyl group of vonoprazan. This may explain its slow dissociation from the H(+) ,K(+) -ATPase and long-lasting inhibition.
CONCLUSION
The binding model provides a template for design of novel potassium-competitive acid blockers.
背景
胃H⁺，K⁺ -ATP酶是胃酸抑制的首选靶点。直到最近，唯一能有效抑制这种ATP酶的药物是质子泵抑制剂（PPIs）。PPIs是酸激活的前体药物，需要酸性环境的保护。一旦被酸激活，PPIs就会与ATP酶的半胱氨酸结合，导致共价、持久的抑制作用。PPIs的血浆半衰期短，且H⁺，K⁺ -ATP酶会持续重新合成，这导致控制夜间胃酸分泌存在困难。PPIs的一种新替代品是吡咯并吡啶类药物沃克帕唑（TAK-438），一种钾竞争性酸阻滞剂（PCAB），它不需要酸性环境的保护。与其他PCABs不同，沃克帕唑作用持续时间长，可实现24小时胃酸分泌控制，其pKa为9.37，亲和力高（Ki = 3.0 nmol/L）。
目的
确定沃克帕唑对胃H⁺，K⁺ -ATP酶的结合选择性，并解释其缓慢解离的原因。
方法
采用放射性测定法确定沃克帕唑在胃腺和壁细胞中的结合情况。分子模拟解释了沃克帕唑从H⁺，K⁺ -ATP酶缓慢解离的原因。
结果
沃克帕唑选择性地与壁细胞结合，与胃酸分泌无关。沃克帕唑结合在膜螺旋4、5和6表面之间的腔前庭。药物向管腔的排出受到跨膜螺旋1（TM1）和跨膜螺旋2（TM2）之间环中的天冬氨酸137和天冬酰胺138的阻碍，这对沃克帕唑磺酰基的移动形成了静电屏障。这可能解释了它从H⁺，K⁺ -ATP酶缓慢解离以及持久抑制的原因。
结论
该结合模型为新型钾竞争性酸阻滞剂的设计提供了模板。
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