用于肠道微生物群介导的药物靶向的定制植物糖缀合物。

Bespoke plant glycoconjugates for gut microbiota-mediated drug targeting.

作者信息

Ma Wei Jen, Wang Changqing, Kothandapani Jagatheeswaran, Luzentales-Simpson Matthew, Menzies Susan C, Bescucci Danisa M, Lange Máximo E, Fraser Alexander S C, Gusse Jenny F, House Kathaleen E, Moote Paul E, Xing Xiaohui, Grondin Julie M, Hui Benjamin Wei-Qiang, Clarke Sandra T, Shelton Tara G, Haskey Natasha, Gibson Deanna L, Martens Eric C, Abbott D Wade, Inglis G Douglas, Sly Laura M, Brumer Harry

机构信息

Department of Pediatrics and BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.

Michael Smith Laboratories and Department of Chemistry, University of British Columbia, Vancouver, BC, Canada.

出版信息

Science. 2025 Jun 26;388(6754):1410-1416. doi: 10.1126/science.adk7633. Epub 2025 May 1.

DOI:10.1126/science.adk7633

PMID:40310938

Abstract

The gut microbiota of mammals possess distinctive metabolic pathways with untapped therapeutic potential. Using molecular insights into dietary fiber metabolism by the human gut microbiota, we designed a targeted drug delivery system, called GlycoCaging, that is based on bespoke glycoconjugates of a complex plant oligosaccharide. GlycoCaging of exemplar anti-inflammatory drugs enabled release of active molecules triggered by specific glycosidases of autochthonous gut bacteria. GlycoCaging ensured that drug efficacy was potentiated, and off-target effects were eliminated in murine models of inflammatory bowel disease. Biochemical and metagenomic analyses of gut microbiota of individual humans confirmed the broad applicability of this strategy.

摘要

哺乳动物的肠道微生物群拥有独特的代谢途径，具有尚未开发的治疗潜力。利用对人类肠道微生物群膳食纤维代谢的分子见解，我们设计了一种靶向给药系统，称为糖笼（GlycoCaging），它基于一种复杂植物寡糖的定制糖缀合物。典型抗炎药物的糖笼化能够实现由本地肠道细菌的特定糖苷酶触发的活性分子释放。在炎症性肠病的小鼠模型中，糖笼化确保了药物疗效的增强，并消除了脱靶效应。对个体人类肠道微生物群的生化和宏基因组分析证实了该策略的广泛适用性。