Morbioli Ilaria, Porkolab Vanessa, Magini Andrea, Casnati Alessandro, Fieschi Franck, Sansone Francesco
Dipartimento di Scienze Chimiche, della Vita e della Sostenibilità Ambientale, Università di Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy.
Université Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, 71 avenue des Martyrs, CS 10090, 38044 Grenoble Cedex 9, France.
Carbohydr Res. 2017 Dec 1;453-454:36-43. doi: 10.1016/j.carres.2017.10.017. Epub 2017 Oct 31.
DC-SIGN is a receptor protruded from the membrane of immature dendritic cells (DCs) that participates in the activation of the immune response through the recognition of pathogen-associated molecular patterns (PAMPs). On the other hand, HIV exploits the interaction between high-mannose structures of its envelope glycoprotein gp120 and DC-SIGN to be transported towards and infect T-cells. DC-SIGN is involved in the recognition process in the form of a tetramer and the multiple exposition of carbohydrate recognition sites (CRSs) is amplified by the formation on the DCs membrane of patches of tetramers. DC-SIGN is then considered an interesting target to fight the virus and multivalent systems exposing multiple copies of ligating units for its CRSs are becoming valuable tools to reach this goal. We herein prepared four mannosylated calix[n]arenes (1a-d) and tested them by Surface Plasmon Resonance (SPR) competition assays as inhibitors of the binding between DC-SIGN and a mannosylated BSA used as model of HIV gp120. ICs in the μM range were found evidencing in particular for compound 1a that, although rather moderate, a multivalent effect is taking place in the inhibition activity of this cluster. A relative potency (rp/n) around 4, respect to the monovalent methyl α-mannoside and normalized for the number of monosaccharide on the scaffold, was observed. This result, compared with previously reported data relative to dendrimers with the same valency, indicates the calixarene as a promising scaffold to build efficient inhibitors for DC-SIGN and, in perspective, for HIV.
DC-SIGN是一种从未成熟树突状细胞（DC）膜突出的受体，它通过识别病原体相关分子模式（PAMP）参与免疫反应的激活。另一方面，HIV利用其包膜糖蛋白gp120的高甘露糖结构与DC-SIGN之间的相互作用，向T细胞运输并感染T细胞。DC-SIGN以四聚体的形式参与识别过程，并且碳水化合物识别位点（CRS）的多次暴露通过DC细胞膜上四聚体斑块的形成而被放大。因此，DC-SIGN被认为是对抗该病毒的一个有吸引力的靶点，而暴露多个CRS连接单元拷贝的多价系统正成为实现这一目标的有价值工具。我们在此制备了四种甘露糖基化杯[n]芳烃（1a-d），并通过表面等离子体共振（SPR）竞争试验将它们作为DC-SIGN与用作HIV gp120模型的甘露糖基化牛血清白蛋白（BSA）之间结合的抑制剂进行测试。发现IC50在微摩尔范围内，特别对于化合物1a而言，尽管相当温和，但在该簇的抑制活性中正在发生多价效应。相对于单价甲基α-甘露糖苷并针对支架上的单糖数量进行归一化，观察到相对效力（rp/n）约为4。与先前报道的关于具有相同价态的树枝状聚合物的数据相比，该结果表明杯芳烃是构建DC-SIGN有效抑制剂以及从长远来看构建HIV有效抑制剂的有前景的支架。
