ArticleNature chemistry2025
Site-specific activation of the proton pump inhibitor rabeprazole by tetrathiolate zinc centres.
Article in Nature chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
6 citing papers in PubMed.
- KCNQ1 disruption alters human neuronal development through mitochondrial and insulin signalling pathways.Communications biology · 2026Article
- Bidentate Metal-Binding Motifs in US FDA Approved Small Molecule Drugs.Journal of medicinal chemistry · 2026Review
- Post-translational modifications of triosephosphate isomerase reveal metabolic vulnerabilities in T-ALL: effect of combining dichloroacetic acid and the PPI rabeprazole.The Biochemical journal · 2026Article
- Antibiotic Cocktail Exacerbates Esomeprazole-Induced Intestinal Dysmotility While Ameliorating Gastric Dyspepsia in Mice.Antibiotics (Basel, Switzerland) · 2025Article
- Secret action of gastric acid controlling drug.Nature chemistry · 2025Article
- Integrative pharmacovigilance and AI-based framework uncovers potential drug triggers in juvenile idiopathic arthritis.Frontiers in immunology · 2025Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors.
Funding
Abstract
Proton pump inhibitors have become top-selling drugs worldwide. Serendipitously discovered as prodrugs that are activated by protonation in acidic environments, proton pump inhibitors inhibit stomach acid secretion by covalently modifying the gastric proton pump. Despite their widespread use, alternative activation mechanisms and potential target proteins in non-acidic environments remain poorly understood. Employing a chemoproteomic approach, we found that the proton pump inhibitor rabeprazole selectively forms covalent conjugates with zinc-binding proteins. Focusing on DENR, a protein with a C4 zinc cluster (that is, zinc coordinated by four cysteines), we show that rabeprazole is activated by the zinc ion and subsequently conjugated to zinc-coordinating cysteines. Our results suggest that drug binding, activation and conjugation take place rapidly within the zinc coordination sphere. Finally, we provide evidence that other proton pump inhibitors can be activated in the same way. We conclude that zinc acts as a Lewis acid, obviating the need for low pH, to promote the activation and conjugation of proton pump inhibitors in non-acidic environments.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.