Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
Nat Commun. 2024 Mar 12;15(1):2226. doi: 10.1038/s41467-024-46481-8.
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.
肝性脑病是一种肝脏疾病引起的神经精神并发症，部分与血氨升高有关。产脲酶细菌在结肠中分解尿素被认为是体内氨生成的主要途径之一，但针对肝性脑病中细菌脲酶的治疗研究有限。本文报道了一种基于羟肟酸的脲酶抑制剂 2-辛炔羟肟酸，其体外活性优于之前研究用于肝性脑病的羟肟酸。2-辛炔羟肟酸在微摩尔浓度范围内具有低细胞毒性和致突变性，并降低了肝脏疾病啮齿动物模型的血氨水平。此外，2-辛炔羟肟酸治疗可降低雄性胆管结扎大鼠小脑谷氨酰胺（氨代谢产物）。原型结肠制剂使雄性犬体内 2-辛炔羟肟酸的系统暴露减少。总的来说，这项工作表明，通过结肠制剂递送至结肠的脲酶抑制剂可能是治疗肝性脑病的一种有前景的方法。
