发现了前所未有的人类斯特科比林结合物的发现
Sungjoon Cho1, Lionel Cheruzel2, Jingwei Cai2
1Department of Drug Metabolism and Pharmacokinetics (S.C., L.C., J.C., L.S., D.Z., S.C.K.) Genentech, Inc., South San Francisco, California; and Hypha Discovery (S.K.W., R.T.G., T.K., J.C.P.S.), Oxfordshire, United Kingdom cho.sungjoon@gene.com.
概括
在人类便中发现了两种新型的inavolisib代谢物,它们是由肠道细菌与斯特科比林的独特化学反应形成的. 这些发现揭示了小分子药物的新代谢途径.
科学领域:
- 药理学 药理学是指药理学的学科.
- 微生物学 微生物学
- 代谢学 代谢学 代谢学
背景情况:
- 伊纳沃利西布是一种氏胺3-激酶抑制剂.
- 肠道微生物组显著影响药物代谢.
- 肠道细菌的血代谢产生了斯特科比林.
研究的目的:
- 在人类便中发现的inavolisib新型代谢物的特征.
- 阐明这些代谢物的形成机制.
- 为了了解inavolisib和肠道衍生菌素之间的相互作用.
主要方法:
- 在人类志愿者中,口服 [14C]inavolisib 的剂量.
- 在实验室中用便同质物化inavolisib.
- 高分辨率质谱学和NMR光谱学用于结构阐明.
- 计算化学以支持拟议的反应机制.
主要成果:
- 检测到两种独特的代谢物 (M18和M19),其特点是母体的分子离子加304Da.
- 结构分析显示,inavolisib的伊米达环与斯特科比林碎片的共价结合.
- 代谢物通过便同质物中的非酶和潜在酶反应生成.
- 提出了一种反应机制,涉及纳沃利西布对斯特科比林的核友攻击,并得到了计算数据的支持.
结论:
- 伊纳沃利西布与肠道微生物组代谢物斯特科比林形成独特的结合物.
- 这些合物是通过化学和可能的酶过程形成的.
- 这种新的代谢途径可能以前被忽视为其他小分子药物.
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