Synthetic Neoglycoconjugates of Hepta- and Nonamannoside Ligands for Eliciting Oligomannose-Specific HIV-1-Neutralizing Antibodies.
Synthetic Neoglycoconjugates of Hepta- and Nonamannoside Ligands for Eliciting Oligomannose-Specific HIV-1-Neutralizing Antibodies.
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DOI：
10.1002/cbic.202200061
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发表时间：
2022-04-05
期刊：
影响因子：
3.2
通讯作者：
Kosma, Paul
中科院分区：
文献类型：
--
作者：
Cattin, Matteo;Bruxelle, Jean-Francois;Ng, Kurtis;Blaukopf, Markus;Pantophlet, Ralph;Kosma, Paul
HIV-1刺突蛋白上的低聚甘露糖型聚糖构成了引发广泛中和抗体（bnAb）的相关表位。在本文中，我们描述了α-和β-连接的七甘露糖基和九甘露糖基配体的改进合成，随后将其转化为BSA和CRM 197新糖缀合物。我们从来自选择的3-O-保护的硫代甲苯基甘露糖苷供体的异头3-叠氮基丙基间隔物糖苷组装配体。使用硫代甲苯基和三氯乙酰亚胺酯糖基供体的[4+3]或[4+5]嵌段合成实现链延伸。随后的整体脱保护产生3-氨基丙基寡糖配体。用β-异头七甘露糖基和九甘露糖基缀合物与选择的HIV-1 bnAb获得的ELISA结合数据显示Fab片段对两种甘露糖基配体的结合相当，但相应的IgG抗体对九糖缀合物的结合较小。这些结果支持先前的观察结果，即完整的Man 9结构可能不是某些寡甘露糖特异性抗体的优选抗原结合基序，并且对糖苷设计具有影响，以引发寡甘露糖靶向的HIV-1中和抗体。异头七-和nonamannoside 3-氨基丙基衍生物制备良好的总产率使用嵌段组装，然后转化成neoglycoconjugates。β-变体的CRM 197缀合物显示与HIV-I中和PGT抗体的Fab相当的结合，但相应IgG抗体对七甘露糖苷的结合更强。
Oligomannose-type glycans on the spike protein of HIV-1 constitute relevant epitopes to elicit broadly neutralizing antibodies (bnAbs). Herein we describe an improved synthesis of α- and β-linked hepta- and nonamannosyl ligands that, subsequently, were converted into BSA and CRM197 neoglycoconjugates. We assembled the ligands from anomeric 3-azidopropyl spacer glycosides from select 3-O-protected thiocresyl mannoside donors. Chain extensions were achieved using [4+3] or [4+5] block synthesis of thiocresyl and trichloroacetimidate glycosyl donors. Subsequent global deprotection generated the 3-aminopropyl oligosaccharide ligands. ELISA binding data obtained with the β-anomeric hepta- and nonamannosyl conjugates with a selection of HIV-1 bnAbs showed comparable binding of both mannosyl ligands by Fab fragments yet lesser binding of the nonasaccharide conjugate by the corresponding IgG antibodies. These results support previous observations that a complete Man9 structure might not be the preferred antigenic binding motif for some oligomannose-specific antibodies and have implications for glycoside designs to elicit oligomannose-targeted HIV-1-neutralizing antibodies. Anomeric hepta- and nonamannoside 3-aminopropyl derivatives were prepared in good overall yields using a block-wise assembly followed by conversion into neoglycoconjugates. CRM197 conjugates of the β-variants showed comparable binding to Fabs of HIV-1 neutralizing PGT antibodies, but stronger binding of the heptamannosides by the corresponding IgG antibodies.
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影响因子：
3.6
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通讯作者：
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