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fluorine, glycans, NMR spectroscopy
Abstract:
Deploying carbohydrate frameshifts to probe glycan-protein interactions is an expansive strategy. Given the prominence of 19F-BioNMR in structural research, fluorinated glycans hold enormous potential in glycomimetic frameshift design. However, challenges associated with the stereocontrolled synthesis of these disruptive actors continue to frustrate advances. To address this, the synthesis of selectively C-2 fluorinated glycans related to the O3b antigen of Klebsiella pneumoniae is disclosed, and their interactions with the lectin Concanavalin A (ConA) are interrogated spectroscopically. To expedite construction, automated glycan assembly (AGA) was employed in which the C(sp3)-F bond was leveraged to control stereoselectivity of α-mannosylation. Subsequent 19F-BioNMR analysis of binding to ConA allowed determination of the respective IC50 values; this revealed a conspicuous frameshift-dependency in which one pattern dominated. This subtle bioisosteric replacement of OH to F clearly manifests itself in physicochemical differences that distinguish fluorinated carbohydrates and their native counterparts. Collectively, this study advocates for the strategic utilisation of the C(sp3)-F bond in the design, construction and analysis of probes to interrogate ubiquitous mannose-binding lectins with therapeutic relevance.
