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. 2015 Dec;42(11-12):1315-26.
doi: 10.1111/apt.13414. Epub 2015 Sep 30.

The Binding Selectivity of Vonoprazan (TAK-438) to the Gastric H+, K+ -ATPase

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The Binding Selectivity of Vonoprazan (TAK-438) to the Gastric H+, K+ -ATPase

D R Scott et al. Aliment Pharmacol Ther. .
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Abstract

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.

Conflict of interest statement

Personal and Funding Interests

Declaration of personal interests: None

Declaration of funding interests: The study was supported by K08DK100661 (EAM), UCLA CDI (EAM), USVA 2I01BX001006 (GS), R01DK105156-01(GS).

Figures

Figure 1
Figure 1
Structures of specific H+,K+-ATPase inhibitors, vonoprazan (A), and the [1,2α] imidazopyridine, SCH28080 (B). Vonoprazan retains high affinity at neutral pH and its amino group was therefore protonated for modeling, while its pyridine nitrogen was left unprotonated. SCH28080 binds with highest affinity at low pH and its binding was modeled in the monoprotonated form.
Figure 2
Figure 2
Vonoprazan binding to resting and stimulated rabbit oxyntic gastric glands. Labeling by [14C]-vonoprazan was independent of the secretory status of gastric oxyntic glands, indicating that inhibition of acid secretion by vonoprazan was immediate since there was no delay due to requirement for acid secretion. Acid secretion was stimulated using histamine and dbcAMP (red) and inhibited by atropine and famotidine (blue).
Figure 3
Figure 3
Vonoprazan labeling of resting and stimulated rabbit parietal cells. Autoradiographic analysis of [14C]-vonoprazan labeling of resting and stimulated gastric parietal cells found no significant difference in labeling (Ttest, p=0.21). Digital darkfield photomicrographs were obtained to quantify the silver grains decorating parietal cells. Silver grains corresponding to the location of [14C]-vonoprazan were quantified using NIH Image J software. Results were reported as mean pixel densities of labeled cells, n=9 for resting cells, n=11 for stimulated cells.
Figure 4
Figure 4
Autoradiographic analysis of [14C]-vonoprazan labeling of resting and stimulated gastric parietal cells. Figure 4A and 4B are representative resting and stimulated parietal cells, respectively, stained with H & E before autoradiography. The secretory canaliculus of the stimulated cell is highlighted by blue arrows. Figures 4C and 4D are photomicrographs of vonoprazan labeled and H & E stained. Figures 4E and 4F are darkfield images showing that the number of silver grains decorating the cytoplasm of acid inhibited and acid stimulated parietal cells are equal, indicating that vonoprazan labels both active and inactive H+,K+-ATPase.
Figure 5
Figure 5
(A) Luminal view of the surface (blue) of the vestibule formed by TM1 (blue), TM2 (light blue), TM3 (green), TM4 (light green), TM5 (yellow), and TM6 (orange). A slot-like cavity at the bottom of the vestibule encloses bound SCH28080 (stick, carbons and surface in orange). The color scheme for the transmembrane helices is maintained in all figures. Methyl (red arrow) and cyanomethyl substituents (orange arrow) of the imidazopyridine ring are buried next to TM4 and TM5, respectively, while the outer edge of the imidazopyridine ring (blue arrow) and oxymethylene bridge (green arrow) are exposed to the solvent. TM3 and the remainder of the membrane domain including TM7, TM8, TM9, TM10, and the beta subunit are omitted for clarity in all figures. TM4 is labeled on both sides of its nonhelical segment near the middle of the membrane. (B) Lowest energy binding site conformation for SCH28080 (stick, carbons in cyan) found by AutoDockVina compared to the one based on biochemical data and energy minimization (stick, carbons in orange). tyr799 and cys813 (ball and stick, carbons in cyan) are shown for reference. Positions of permissible substituent addition on the imidazopyridine ring (left green star) and of the diol bridge (right green star) are shown between aromatic rings in the imidazopyridines. Substituents are size-restricted at the buried edge of the imidazopyridine ring (maximum size is an ethyl group in the R3 position, lower red star and methyl in R2, upper red star).
Figure 6
Figure 6
(A) Surfaces of the luminal vestibule (blue) and vonoprazan (stick, carbons in orange). The inhibitor is proposed to fit in the slot at the bottom of the vestibule as suggested for SCH28080 with the methylamino group (red arrow) next to TM5, the sulfonyl group (yellow arrow) facing TM2 near the start of TM6, and the fluorophenyl ring between TM5 and TM6 (helices colored as in figure 2). Only the outer edge of the fluorophenyl ring (center) is exposed to the solvent. (B) Proposed binding site for vonoprazan (surface and stick with carbons in orange) with residues whose mutation affect binding (ball and stick) in cyan. The inhibitor fits in the loop between TM5 and TM6 (light orange and dark orange ribbons, respectively) on one end and TM1 (blue ribbon) and TM4 (green ribbon) on the other (TM3 omitted). Mutation of tyr799 or ala335 (ball and stick) on one side of the bound inhibitor severely affect binding. Methoxy substitution in the 6 position of the pyridine ring (red circle) has been reported to give retention of high affinity H+,K+-ATPase inhibition while replacement of fluorine in the 2 position of the phenyl ring (blue circle) with methoxy gives a loss of more than 100-fold in affinity. (C) A nearly identical pose for vonoprazan (stick, carbons in blue) docking is found by an unbiased scoring algorithm (AutoDockVina). As found for the energy minimized conformation in 6B, the inhibitor is oriented in the binding space with the methylamino group in next to an expanded turn in TM5 produced by pro798 and hydrogen bonding to the backbone carbonyl of glu795 (blue arrow). The sulfonyl oxygens face the sulfhydryl hydrogen from cys813. Asp137 and asn138 present a likely electrostatic barrier to the sulfonyl oxygens (red arrow) of the inhibitor for movement toward the open end of the vestibule and exit to the lumen (green arrow).

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