Inhibition of urease-mediated ammonia production by 2-octynohydroxamic acid in hepatic encephalopathy

Diana Evstafeva, Filip Ilievski, Yinyin Bao, Zhi Luo, Boris Abramovic, Sunghyun Kang, Christian Steuer, Elita Montanari, Tommaso Casalini, Dunja Simicic, Dario Sessa, Stefanita-Octavian Mitrea, Katarzyna Pierzchala, Cristina Cudalbu, Chelsie E. Armbruster and Jean-Christophe Leroux ()
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Diana Evstafeva: Department of Chemistry and Applied Biosciences, ETH Zurich
Filip Ilievski: Department of Chemistry and Applied Biosciences, ETH Zurich
Yinyin Bao: Department of Chemistry and Applied Biosciences, ETH Zurich
Zhi Luo: Department of Chemistry and Applied Biosciences, ETH Zurich
Boris Abramovic: Department of Chemistry and Applied Biosciences, ETH Zurich
Sunghyun Kang: Department of Chemistry and Applied Biosciences, ETH Zurich
Christian Steuer: Department of Chemistry and Applied Biosciences, ETH Zurich
Elita Montanari: Department of Chemistry and Applied Biosciences, ETH Zurich
Tommaso Casalini: Department of Chemistry and Applied Biosciences, ETH Zurich
Dunja Simicic: CIBM Center for Biomedical Imaging
Dario Sessa: University Hospitals Geneva and University of Geneva
Stefanita-Octavian Mitrea: CIBM Center for Biomedical Imaging
Katarzyna Pierzchala: CIBM Center for Biomedical Imaging
Cristina Cudalbu: CIBM Center for Biomedical Imaging
Chelsie E. Armbruster: State University of New York at Buffalo
Jean-Christophe Leroux: Department of Chemistry and Applied Biosciences, ETH Zurich

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Hepatic encephalopathy is a neuropsychiatric complication of liver disease which is partly associated with elevated ammonemia. Urea hydrolysis by urease-producing bacteria in the colon is often mentioned as one of the main routes of ammonia production in the body, yet research on treatments targeting bacterial ureases in hepatic encephalopathy is limited. Herein we report a hydroxamate-based urease inhibitor, 2-octynohydroxamic acid, exhibiting improved in vitro potency compared to hydroxamic acids that were previously investigated for hepatic encephalopathy. 2-octynohydroxamic acid shows low cytotoxic and mutagenic potential within a micromolar concentration range as well as reduces ammonemia in rodent models of liver disease. Furthermore, 2-octynohydroxamic acid treatment decreases cerebellar glutamine, a product of ammonia metabolism, in male bile duct ligated rats. A prototype colonic formulation enables reduced systemic exposure to 2-octynohydroxamic acid in male dogs. Overall, this work suggests that urease inhibitors delivered to the colon by means of colonic formulations represent a prospective approach for the treatment of hepatic encephalopathy.

Date: 2024
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DOI: 10.1038/s41467-024-46481-8

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