Preparation and Evaluation of Colon-Targeted Prodrugs of the Microbial Metabolite 3-Indolepropionic Acid as an Anticolitic Agent,Molecular Pharmaceutics

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Preparation and Evaluation of Colon-Targeted Prodrugs of the Microbial Metabolite 3-Indolepropionic Acid as an Anticolitic Agent
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2021-03-04 , DOI: 10.1021/acs.molpharmaceut.0c01228
Hanju Lee ₁ , Sohee Park ₁ , Sanghyun Ju ₁ , Soojin Kim ₁ , Jin-Wook Yoo ₁ , In-Soo Yoon ₁ , Do Sik Min ₂ , Yunjin Jung ₁

Affiliation

Microbial metabolites play a critical role in mucosal homeostasis by mediating physiological communication between the host and colonic microbes, whose perturbation may lead to gut inflammation. The microbial metabolite 3-indolepropionic acid (3-IPA) is one such communication mediator with potent antioxidative and anti-inflammatory activity. To apply the metabolite for the treatment of colitis, 3-IPA was coupled with acidic amino acids to yield colon-targeted 3-IPA, 3-IPA-aspartic acid (IPA-AA) and 3-IPA-glutamic acid (IPA-GA). Both conjugates were activated to 3-IPA in the cecal contents, which occurred faster for IPA-AA. Oral gavage of IPA-AA (oral IPA-AA) delivered a millimolar concentration of IPA-AA to the cecum, liberating 3-IPA. In a 2,4-dinitrobenzene sulfonic acid (DNBS)-induced rat colitis model, oral IPA-AA ameliorated rat colitis and was less effective than sulfasalazine (SSZ), a current anti-inflammatory bowel disease drug. To enhance the anticolitic activity of 3-IPA, it was azo-linked with the GPR109 agonist 5-aminonicotinic acid (5-ANA) to yield IPA-azo-ANA, expecting a mutual anticolitic action. IPA-azo-ANA (activated to 5-ANA and 2-amino-3-IPA) exhibited colon specificity in in vitro and in vivo experiments. Oral IPA-azo-ANA mitigated colonic damage and inflammation and was more effective than SSZ. These results suggest that colon-targeted 3-IPA ameliorated rat colitis and its anticolitic activity could be enhanced by codelivery of the GPR109A agonist 5-ANA.

中文翻译：

微生物代谢产物 3-吲哚丙酸作为抗结肠药的结肠靶向前药的制备和评价

微生物代谢物通过介导宿主和结肠微生物之间的生理通讯，在粘膜稳态中发挥关键作用，肠道微生物的扰动可能导致肠道炎症。微生物代谢物 3-吲哚丙酸 (3-IPA) 是一种具有有效抗氧化和抗炎活性的通讯介质。为了将代谢物用于治疗结肠炎，将 3-IPA 与酸性氨基酸结合以产生靶向结肠的 3-IPA、3-IPA-天冬氨酸 (IPA-AA) 和 3-IPA-谷氨酸 (IPA-GA) ）。两种缀合物在盲肠内容物中都被激活为 3-IPA，IPA-AA 发生得更快。口服 IPA-AA（口服 IPA-AA）向盲肠输送毫摩尔浓度的 IPA-AA，释放 3-IPA。在 2,4-二硝基苯磺酸 (DNBS) 诱导的大鼠结肠炎模型中，口服 IPA-AA 改善了大鼠结肠炎，但效果不如柳氮磺吡啶（SSZ），后者是一种当前的抗炎性肠病药物。为了增强 3-IPA 的抗结肠炎活性，将其与 GPR109 激动剂 5-氨基烟酸 (5-ANA) 偶氮连接以产生 IPA-偶氮-ANA，期待相互的抗结肠炎作用。IPA-azo-ANA（激活为 5-ANA 和 2-amino-3-IPA）在体外和体内实验中表现出结肠特异性。口服 IPA-azo-ANA 可减轻结肠损伤和炎症，并且比 SSZ 更有效。这些结果表明，靶向结肠的 3-IPA 可改善大鼠结肠炎，并且可以通过 GPR109A 激动剂 5-ANA 的共同递送来增强其抗结肠炎活性。它与 GPR109 激动剂 5-氨基烟酸 (5-ANA) 偶氮连接以产生 IPA-偶氮-ANA，期待相互抗结肠炎作用。IPA-azo-ANA（激活为 5-ANA 和 2-amino-3-IPA）在体外和体内实验中表现出结肠特异性。口服 IPA-azo-ANA 可减轻结肠损伤和炎症，并且比 SSZ 更有效。这些结果表明，靶向结肠的 3-IPA 可改善大鼠结肠炎，并且可以通过 GPR109A 激动剂 5-ANA 的共同递送来增强其抗结肠炎活性。它与 GPR109 激动剂 5-氨基烟酸 (5-ANA) 偶氮连接以产生 IPA-偶氮-ANA，期待相互抗结肠炎作用。IPA-azo-ANA（激活为 5-ANA 和 2-amino-3-IPA）在体外和体内实验中表现出结肠特异性。口服 IPA-azo-ANA 可减轻结肠损伤和炎症，并且比 SSZ 更有效。这些结果表明，靶向结肠的 3-IPA 可改善大鼠结肠炎，并且可以通过 GPR109A 激动剂 5-ANA 的共同递送来增强其抗结肠炎活性。

更新日期：2021-04-05

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