title: The binding selectivity of vonoprazan (TAK-438) to the gastric H+, K+ -ATPase.
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).
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  The binding model provides a template for design of novel potassium-competitive acid blockers.
authors.affiliation: Department of Physiology, DGSOM at UCLA, Los Angeles, CA, USA.|VA GLAHS, Los Angeles, CA, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Scott
authors.affiliation: VA GLAHS, Los Angeles, CA, USA.|Department of Medicine, DGSOM at UCLA, Los Angeles, CA, USA.
authors.forename: K B
authors.initials: KB
authors.lastname: Munson
authors.affiliation: VA GLAHS, Los Angeles, CA, USA.|Department of Pediatrics, DGSOM at UCLA, Los Angeles, CA, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Marcus
authors.affiliation: Pathology and Laboratory Medicine Service, VA Long Beach Healthcare System, Long Beach, CA, USA.
authors.forename: N W G
authors.initials: NW
authors.lastname: Lambrecht
authors.affiliation: Department of Physiology, DGSOM at UCLA, Los Angeles, CA, USA.|VA GLAHS, Los Angeles, CA, USA.|Department of Medicine, DGSOM at UCLA, Los Angeles, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Sachs
mesh_terms: D000818:Animals; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism*; D006207:Half-Life; D008297:Male; D010295:Parietal Cells, Gastric / Q000378:metabolism; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000378:metabolism*; D011817:Rabbits; D013449:Sulfonamides / Q000378:metabolism*
chemical_list: C552956:1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; D054328:Proton Pump Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; D017506:H(+)-K(+)-Exchanging ATPase