The binding selectivity of vonoprazan (TAK-438) to the gastric H+,K+-ATPase

BackgroundThe 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 pK(a) of 9.37 and high affinity (K-i = 3.0 mol/L). AimTo determine binding selectivity of vonoprazan for the gastric H+,K+-ATPase and to explain its slow dissociation. MethodsGastric gland and parietal cell binding of vonoprazan was determined radiometrically. Molecular modelling explained the slow dissociation of vonoprazan from the H+,K+-ATPase. ResultsVonoprazan 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. ConclusionThe binding model provides a template for design of novel potassium-competitive acid blockers.