Exploring Siglec-glycan ligand interactions using chemoenzymatic approaches

使用化学酶方法探索 Siglec-聚糖配体相互作用

• 批准号: 10297728
• 负责人: Peng Wu
• 金额: $ 81.53万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-04 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297728
• 关键词: 2019-nCoV; Advanced Malignant Neoplasm; Affinity; Anti-Inflammatory Agents; Binding; Binding Proteins; Biochemical Genetics; CTLA4 gene; Cancer Patient; Cell Death; Cell Line; Cell surface; Cells; Clinical; Clinical Trials; Development; Elements; Engineering; Epitopes; FDA approved; Family; Goals; Immune; Immune checkpoint inhibitor; Immune signaling; Immune system; Immunoglobulins; Immunotherapy; Inflammation; Inflammatory; Lectin; Ligand Binding; Ligands; Malignant Neoplasms; Mediating; Membrane Glycoproteins; Modality; Molecular; Myeloid Cells; Natural Killer Cells; Pathology; Patients; Pattern; Polysaccharides; Process; Proteins; Receptor Activation; Regulation; Relapse; Reporter; Role; SARS-CoV-2 infection; Sialic Acids; Side; Signal Transduction; Syndrome; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Tumor Immunity; Tyrosine; Virus Diseases; Xenograft Model; anti-PD-1; anti-cancer; base; cancer therapy; cancer type; cell killing; cytotoxic; cytotoxicity; design; glycosylation; immune activation; immune checkpoint; immune checkpoint blockade; immunological synapse; immunoregulation; invention; macrophage; mast cell; nanoparticle; neoplastic cell; novel therapeutics; programmed cell death protein 1; receptor; receptor binding; recruit; response; sialic acid binding Ig-like lectin; tool; tumor

PROJECT SUMMARY/ABSTRACT Regulation of the immune system is substantially influenced by glycosylation. Cell-surface glycans tune ligand-receptor binding and set a threshold for initiating the downstream signaling for immune cell activation. Siglecs (sialic acid-binding immunoglobulin-type lectins) are a family of regulatory receptors involved in these processes. A Siglec can bind to both cis and trans sialylated glycan ligands that are expressed on the same or interacting cells, respectively. The binding of Siglecs with their ligands can either segregate Siglecs from activation receptors or move them closer. The ability of inhibitory Siglecs to modulate activation receptors is regulated by spatial proximity: recruiting Siglecs to the immune synapse in the proximity of activation receptors would trigger inhibitory signaling to suppress immune-system activation, whereas moving Siglecs away from activation receptors would enable optimal signaling through activation receptors. For the above reasons, recently, Siglecs have been described as glyco-immune checkpoints. Through their interaction with sialylated glycans aberrantly expressed on tumor cells, innate immune cell-associated Siglecs trigger signaling cascades to inhibit immune-system activation. Likewise, Siglecs upregulated on tumor cells interact with yet-to-be identified T-cell membrane glycoproteins to suppress T cell anti-tumor functions. On the positive side, however, inhibitory signaling through Siglecs curbs inflammation during cell death induced by viral infection. Despite these intriguing observations, the mechanisms underlying the above processes are just starting to be elucidated. The overarching goal of this project is to use a combination of chemoenzymatic, biochemical and genetic tools to explore Siglec-glycan ligand interactions and their therapeutic implication. In Aim 1, we will design Siglec-based chimeric switch receptors and convert inhibitory Siglecs into activation receptors. In Aim 2, we will use a cell-based glycan array platform to screen for high-affinity and specific ligands of Siglecs. Once identified, we will explore their utilities to suppress or harness the inhibitory Siglec signaling for therapeutic applications. Finally, we will use our chemoenzymatic tools to investigate how the Siglec-cis ligand interaction is involved in mediating the Siglec–trans ligand interaction and accordingly immune cell activation (Aim 3).

项目总结/摘要 免疫系统的调节基本上受糖基化的影响。细胞表面聚糖调节 配体-受体结合，并设定用于启动免疫细胞活化的下游信号传导的阈值。 Siglecs（唾液酸结合免疫球蛋白型凝集素）是参与这些调节的调节受体家族。 流程. Siglec可以结合在相同或不同的载体上表达的顺式和反式唾液酸化聚糖配体。 相互作用的细胞。Siglecs与其配体的结合可以将Siglecs与它们的配体分离。 激活受体或使它们靠近。抑制性Siglecs调节活化受体的能力是 受空间邻近性调节：在激活受体附近将Siglecs募集到免疫突触 将触发抑制信号，抑制免疫系统激活，而移动Siglecs远离 活化受体将通过活化受体实现最佳信号传导。 由于上述原因，最近，Siglecs已被描述为糖免疫检查点。通过 它们与肿瘤细胞上异常表达的唾液酸化聚糖的相互作用，先天免疫细胞相关 Siglecs触发信号级联以抑制免疫系统激活。同样，Siglecs在肿瘤细胞中上调， 细胞与尚未鉴定的T细胞膜糖蛋白相互作用以抑制T细胞抗肿瘤功能。 然而，从积极的方面来看，通过Siglecs的抑制性信号传导抑制了细胞死亡期间的炎症 由病毒感染引起的。尽管有这些有趣的观察结果，上述机制的基础 过程才刚刚开始被阐明。 该项目的总体目标是使用化学酶，生物化学和 基因工具来探索Siglec-聚糖配体相互作用及其治疗意义。在目标1中，我们 设计基于Siglec的嵌合开关受体，并将抑制性Siglec转化为激活受体。在Aim中 2、我们将使用基于细胞的聚糖阵列平台来筛选Siglecs的高亲和力和特异性配体。一旦 我们将探索它们抑制或利用抑制性Siglec信号传导用于治疗的效用。 应用.最后，我们将使用我们的化学酶工具来研究Siglec-cis配体相互作用是如何进行的。 参与介导Siglec-反式配体相互作用并因此参与免疫细胞活化（Aim 3）。