Thermodynamics-guided Design of Multivalent Ligands for the Myeloid C-type Lectin Receptor DC-SIGN

髓样C型凝集素受体DC-SIGN通过介导与病毒包膜糖蛋白的相互作用促进某些类型的免疫细胞的感染和病毒颗粒的传播。该受体与病毒病原体如SARS-CoV-2、埃博拉、HIV、寨卡和登革热的多种感染的病理学有关。能够抑制病毒与DC-SIGN相互作用的基于碳水化合物的化合物代表了开发广泛作用的抗病毒治疗剂的有希望的方法。通过针对最终在宿主基因组中保守的分子靶标，这些分子可以有助于早期遏制未来具有大流行潜力的病毒感染。该项目旨在开发DC-SIGN的寡价配体，其能够同时结合同源四聚体受体的多个结合位点。设计此类分子的一个特别挑战是选择合适的化学接头，其将寡价配体的中心支架与糖模拟物结合表位连接。柔性接头的使用通常与结合亲和力的显著降低相关，这是由于结合时构象自由度的损失。因此，所提出的化合物的优化将包括为给定系统合成定制的刚性接头。然后，与DC-SIGN的各自相互作用的热力学表征将产生关于寡价识别的驱动力的有价值的信息。在病毒感染的细胞模型中的进一步生物学实验将产生关于所开发化合物的效力的信息。本文提出的寡价糖模拟物联合收割机结合了单价碳水化合物类似物和复杂多价系统的优点。除了高度的选择性和改善的结合焓之外，结合表位的靶向呈递将利用多价亲和力增强，同时使熵罚分最小化。

The myeloid C-type lectin receptor DC-SIGN promotes the infection of certain types of immune cells and dissemination of virus particles by mediating interactions with viral envelope glycoproteins. The receptor has been implicated in the pathology of multiple infections with viral pathogens such as SARS-CoV-2, Ebola, HIV, Zika, and Dengue. Carbohydrate-based compounds that are able to inhibit the interactions of viruses with DC-SIGN represent a promising approach towards the development of broadly acting antiviral therapeutics. By addressing molecular targets, which are ultimately conserved in the host genome, these molecules could contribute to the early containment of future viral infections with pandemic potential. This project aims to develop oligovalent ligands for DC-SIGN, which are able to bind multiple binding sites of the homotetrameric receptor simultaneously. A particular challenge in the in the design of such molecules is the selection of appropriate chemical linkers that connect the central scaffold of the oligovalent ligand with the glycomimetic binding epitope. The use of flexible linkers is typically associated with a significant reduction in binding affinity due to the loss of conformational degrees of freedom upon binding. Thus, the optimization of the proposed compounds will encompass the synthesis of tailor-made rigid linkers for the given system. A thermodynamic characterization of the respective interactions with DC-SIGN will then yield valuable information about the driving forces underlying oligovalent recognition. Further biological experiments in cellular models of viral infection will yield information about the potency of the developed compounds. The oligovalent glycomimetics presented here combine the advantages of monovalent carbohydrate analogs and complex polyvalent systems. Besides a high degree of selectivity and improved binding enthalpy, a targeted presentation of binding epitopes will harness multivalent affinity enhancement, while simultaneously minimizing entropic penalties.