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

热力学指导的骨髓 C 型凝集素受体 DC-SIGN 多价配体设计

• 批准号: 532758733
• 负责人: Professor Dr. Jonathan Cramer
• 金额: --
• 依托单位: Institut für Pharmazeutische und Medizinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/532758733?language=en
• 关键词: Thermodynamics; guided; Design; Multivalent; Ligands

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.

髓系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免疫细胞的感染和病毒颗粒的传播。该受体与SARS-CoV-2、埃博拉病毒、艾滋病毒、寨卡病毒和登革热等病毒性病原体的多种感染病理有关。以碳水化合物为基础的化合物能够抑制病毒与DC-SIGN的相互作用，这是开发广谱抗病毒治疗药物的一种很有前途的方法。通过处理最终在宿主基因组中保守的分子靶点，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。本项目旨在开发DC-SIGN的寡价配体，能够同时结合同四聚体受体的多个结合位点。设计这种分子的一个特别的挑战是选择合适的化学连接体，将低价配体的中心支架与糖拟结合表位连接起来。由于结合时构象自由度的丧失，柔性连接体的使用通常伴随着结合亲和性的显著降低。因此，所提出的化合物的优化将包括为给定系统量身定制的刚性连接剂的合成。对各自与DC-SIGN相互作用的热力学表征将产生有关寡价识别驱动力的有价值的信息。在病毒感染的细胞模型中进行进一步的生物学实验将产生有关所开发化合物效力的信息。本文介绍的低价糖模拟物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进的结合焓外，结合表位的靶向呈现将利用多价亲和力增强，同时最大限度地减少熵损失。