stain between the exomethylene group and the substituent at C2 should occur, which would favor a change to a 4S2 or 4H5-type conformation. This conformational flexibility might be relevant to the high inhibitory potency. In other words, the sialidase does cleave the O-glycoside bond, but very slowly, and so covalent bond formation would compete with the hydrolysis reaction5).We expect that such a pseudo-glycan MBIs based on native glycan structures will be a useful molecular tool to track glycan degradation at the cellular level. In this research project, we are aiming to extend this concept, and to develop new pseudo-glycans that can contribute to glycobiology research. We have already achieved several interesting results. We would like to thank the Mizutani Foundation for Glycoscience for financial support of this research.Development of novel mechanism-based inhibitors for glycohydrolasesGo HiraiFigure 3.A) Structures of 4, 5 and 7 and their inhibitory activities towards several exo-sialidasesB) Structure of 6 and covalent-bond formation with NanI.formation with sialidase was observed in cell lysates. Notably, these molecules showed significant inhibitory activity for exo-sialidases. Normally, the inhibitory potency of substrate-type analogues is not so high. Surprisingly, however, 4 and 5 exhibited remarkable inhibitory activity and selectivity for NanI and human sialidase NEU2. The inhibitory effects are 50 to 100 times higher than that of DANA (7) without additional modification of the substituents on the sialic acid. Further experiments led us to a plausible mechanism for the potent inhibition of exo-sialidase by the new pseudo-glycans. The high inhibitory potency of our 3-exoSia-containing pseudo-glycans indicates that they bind strongly to exo-sialidase. Thus, they probably have a substrate-like 2C5 conformation, but allylic References1) Hirai G, Kato M, Koshino H, Nishizawa E, Oonuma K, Ota E, Watanabe T, Hashizume D, Tamura Y, Okada M, Miyagi T, Sodeoka M, Ganglioside GM3 Analogues Containing Monofluoromethylene-Linked Sialoside: Synthesis, Stereochemical Effects, Conformational Behavior, and Biological Activities, JACS Au (1): 137-146, 2021.2) Takeda D, Yoritate M, Yasutomi H, Chiba S, Moriyama T, Yokoo A, Usui K, Hirai G, β-Glycosyl Trifluoroborates as Precursors for Direct α-C-Glycosylation: Synthesis of 2-Deoxy-α-C-glycosides. Org. Lett. (23): 1940-1944, 2021.3) Hidaka Y, Kiya N, Yoritate M, Usui K, Hirai G, Synthesis of CH2-linked α-galactosylceramide and its glucose analogues through glycosyl radical-mediated direct C-glycosylation, Chem. Commun. (56): 4712-4715. 2020.4) Kiya N, Hidaka Y, Usui K, Hirai G, Synthesis of CH2-Linked α(1,6)-Disaccharide Analogues by α-Selective Radical Coupling C-Glycosylation, Org. Lett. (21): 1588-1592, 2019.5) Fukazawa R, Oonuma K, Maeda R, Uezono K, Kato M, Koshino H, Morita M, Miyagi T, Sodeoka M, Hirai G, 3-Exomethylene Sialic Acid Disaccharides as Substrate-Type Mechanism-Based Sialidase Inhibitors, ChemRxiv, doi: 10.26434/chemrxiv-2022-vd8cr.124To be published at a later date.
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