The binding selectivity of vonoprazan (TAK-438) to the gastric H+, K+ -ATPase.
The binding selectivity of vonoprazan (TAK-438) to the gastric H+, K+ -ATPase.
复制标题
DOI：
10.1111/apt.13414
复制
发表时间：
2015-12
影响因子：
7.6
通讯作者：
Sachs G
中科院分区：
文献类型：
--
作者：
Scott DR;Munson KB;Marcus EA;Lambrecht NW;Sachs G
胃H+，K+-ATP酶是抑酸的首选靶点。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（PPI）。PPI是需要酸保护的酸活化前药。一旦酸激活，PPI与ATP酶的半胱氨酸结合，产生共价的持久抑制作用。PPI的血浆半衰期短和H+，K+-ATP酶的持续从头合成导致难以控制夜间酸分泌。PPI的一种新替代药物是吡咯并吡啶沃诺拉赞（TAK-438），这是一种不需要酸保护的钾竞争性酸阻断剂（PCAB）。与其他PCAB相比，沃诺拉赞的作用持续时间较长，可在24小时内控制酸分泌，pKa较高（9.37），亲和力较高（Ki = 3.0 ηM）。确定沃诺拉赞对胃H+，K+-ATP酶的结合选择性，并解释其缓慢解离。通过放射性测定法测定沃诺拉赞的胃腺和壁细胞结合率。分子建模解释了沃诺拉赞从H+，K+-ATP酶上缓慢解离的原因。沃诺拉赞选择性地与壁细胞结合，不依赖于酸分泌。沃诺拉赞结合在膜螺旋4、5和6表面之间的腔前庭中。TM 1和TM 2之间的环中的asp 137和asn 138阻碍药物退出管腔，这对沃诺拉赞磺酰基的移动提供了静电屏障。这可能解释了它与H ~+，K ~+-ATP酶的缓慢解离和持久抑制。结合模型为新型PCAB的设计提供了模板。
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 nighttime 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 hour control of acid secretion, a high pKa of 9.37 and high affinity (Ki = 3.0 ηM). To determine binding selectivity of vonoprazan for the gastric H+,K+-ATPase and to explain its slow dissociation. Gastric gland and parietal cell binding of vonoprazan was determined radiometrically. Molecular modeling explained the slow dissociation of vonoprazan from the H+,K+-ATPase. 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. The binding model provides a template for design of novel PCABs.