Bertolotti Benedetta, Sutkeviciute Ieva, Ambrosini Martino, Ribeiro-Viana Renato, Rojo Javier, Fieschi Franck, Dvořáková Hana, Kašáková Martina, Parkan Kamil, Hlaváčková Martina, Nováková Kateřina, Moravcová Jitka
Department of Chemistry of Natural Compounds, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague, Czech Republic.
Org Biomol Chem. 2017 May 10;15(18):3995-4004. doi: 10.1039/c7ob00322f.
The C-type lectin DC-SIGN expressed on immature dendritic cells is a promising target for antiviral drug development. Previously, we have demonstrated that mono- and divalent C-glycosides based on d-manno and l-fuco configurations are promising DC-SIGN ligands. Here, we described the convergent synthesis of C-glycoside dendrimers decorated with 4, 6, 9, and 12 α-l-fucopyranosyl units and with 9 and 12 α-d-mannopyranosyl units. Their affinity against DC-SIGN was assessed by surface plasmon resonance (SPR) assays. For comparison, parent O-glycosidic dendrimers were synthesized and tested, as well. A clear increase of both affinity and multivalency effect was observed for C-glycomimetics of both types (mannose and fucose). However, when dodecavalent C-glycosidic dendrimers were compared, there was no difference in affinity regarding the sugar unit (l-fuco, IC 17 μM; d-manno, IC 12 μM). For the rest of glycodendrimers with l-fucose or d-mannose attached by the O- or C-glycosidic linkage, C-glycosidic dendrimers were significantly more active. These results show that in addition to the expected physiological stability, the biological activity of C-glycoside mimetics is higher in comparison to the corresponding O-glycosides and therefore these glycomimetic multivalent systems represent potentially promising candidates for targeting DC-SIGN.
未成熟树突状细胞上表达的C型凝集素DC-SIGN是抗病毒药物开发的一个有前景的靶点。此前，我们已经证明基于d-甘露糖和l-岩藻糖构型的单价和二价C-糖苷是有前景的DC-SIGN配体。在此，我们描述了用4、6、9和12个α-l-呋喃岩藻糖基单元以及9和12个α-d-甘露糖基单元修饰的C-糖苷树枝状大分子的汇聚合成。通过表面等离子体共振（SPR）分析评估了它们对DC-SIGN的亲和力。为了进行比较，还合成并测试了母体O-糖苷树枝状大分子。对于两种类型（甘露糖和岩藻糖）的C-糖模拟物，均观察到亲和力和多价效应明显增加。然而，当比较十二价C-糖苷树枝状大分子时，就糖单元而言（l-岩藻糖，IC 17 μM；d-甘露糖，IC 12 μM），亲和力没有差异。对于其余通过O-或C-糖苷键连接l-岩藻糖或d-甘露糖的糖树枝状大分子，C-糖苷树枝状大分子的活性明显更高。这些结果表明，除了预期的生理稳定性外，C-糖苷模拟物的生物活性比相应的O-糖苷更高，因此这些糖模拟多价系统代表了靶向DC-SIGN的潜在有前景的候选物。
