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

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High Resolution Image Download MS PowerPoint Slide 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.

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