Chemoselective Modification of Reducing 2‑Acetamido Sugars Enables Facile Functionalization of Diverse Peptidoglycan Fragments Derived from the Gut Microbiota.

IF 8.7 Q1 CHEMISTRY, MULTIDISCIPLINARY
JACS Au Pub Date : 2025-08-21 eCollection Date: 2025-09-22 DOI:10.1021/jacsau.5c00790
Christopher Adamson, Evan Wei Long Ng, Allan Wee Ren Ng, Shiliu Feng, Yuan Qiao
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引用次数: 0

Abstract

Gut microbiota-derived peptidoglycan fragments (PGNs) are key signaling molecules in microbiota-host crosstalk. Efficient strategies to functionalize natural, unprotected PGN molecules are highly desirable for advancing the biological studies of PGNs. In this work, we developed a facile chemoselective strategy to derivatize the anomeric C1 position of reducing 2-acetamido sugars, a characteristic shared by most PGNs that contain reducing N-acetylmuramic acid. Upon treatment with imidazole-dithiocarbamate-azide (IDA), we showed that natural reducing 2-acetamido PGNs are readily converted to oxazoline intermediates under aqueous conditions. Serendipitously, we discovered that simply freeze-drying the reaction mixture promotes glycosidation of the oxazoline glycosyl donor, leading to PGN-DTC-azide products with high stereoselectivity and yields. Importantly, our chemoselective azidation strategy shows a broad substrate scope, including diverse gut microbiota-derived PGNs, such as muropeptides and natural oligosaccharides. The azido moiety in PGN-DTC-azides serves as a versatile handle for further functionalization, leading to fluorescent or photo-cross-linking PGN probes that maintain the immunological activities of natural PGNs. Importantly, we demonstrate the successful generation of the IgG1 monoclonal antibody 7F8 in mice, which specifically recognizes GlcNAc-MurNAc-DTC-azide as its antigen. Together, we present a simple and unprecedented chemoselective modification of reducing 2-acetamido sugars in unprotected forms via simple freeze-drying, offering attractive tools for studying gut microbiota-derived PGNs and other carbohydrates.

2 -乙酰氨基糖的化学选择性修饰使来自肠道微生物群的多种肽聚糖片段容易功能化。
肠道菌群衍生的肽聚糖片段(PGNs)是菌群-宿主串扰的关键信号分子。有效的策略来功能化天然的,无保护的PGN分子是非常可取的,以推进PGN的生物学研究。在这项工作中,我们开发了一种简单的化学选择策略来衍生还原性2-乙酰氨基糖的端粒C1位置,这是大多数含有还原性n -乙酰氨基酸的pgn所共有的特征。用咪唑-二硫代氨基甲酸乙酯叠氮化物(IDA)处理后,我们发现天然还原性2-乙酰氨基PGNs在水条件下很容易转化为恶唑啉中间体。我们偶然发现,简单的冷冻干燥反应混合物可以促进恶唑啉糖基供体的糖苷化,从而产生具有高立体选择性和产率的pgn - dtc叠氮化产物。重要的是,我们的化学选择性叠氮化策略显示出广泛的底物范围,包括多种肠道微生物衍生的pgn,如多肽和天然低聚糖。叠氮化物中的叠氮素部分作为进一步功能化的通用手柄,导致荧光或光交联的PGN探针维持天然PGN的免疫活性。重要的是,我们证明了在小鼠中成功生成IgG1单克隆抗体7F8,该抗体特异性识别glcnac - murnac - dtc -叠氮化物作为其抗原。总之,我们提出了一种简单的、前所未有的化学选择性修饰,通过简单的冷冻干燥来还原无保护形式的2-乙酰氨基糖,为研究肠道微生物来源的PGNs和其他碳水化合物提供了有吸引力的工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
9.10
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0.00%
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10 weeks
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