小柯机器人

美国斯坦福大学医学院K. Christopher Garcia课题组宣布他们研发了替代细胞因子激动剂的筛选方法。2022年3月23日出版的《细胞》杂志发表了这项成果。

研究人员研发了一种通过使用模块化配体来发现细胞因子替代激动剂的策略，该配体利用诱导相邻和受体二聚体几何形状作为适用于高通量筛选的药理学指标。研究人员将VHH和scFv用于人白介素2/15、I型干扰素和白介素10受体，生成了单链双特异性配体的组合矩阵，这些配体表现出多种功能活性，包括通过替代干扰素产生对SARS-CoV-2的有效抑制。IL-2R:VHH复合物的晶体结构揭示了受体二聚体几何形状的变化如何导致功能多样的信号输出。

这种模块化平台使替代配体工程成为可能，这些配体产生IL-2R/IL-10R异二聚体组装，这种异二聚体并非天然存在，通过T细胞和自然杀伤（NK）细胞上的pSTAT5发出信号。这种植根于相邻诱导原则的“细胞因子药物化学”方法可应用于发现许多配体-受体系统的多样化激动剂。

研究人员表示，细胞因子是强大的免疫调节剂，通过受体二聚化开启信号传导，但天然细胞因子作为治疗剂存在结构限制。

附：英文原文

Title: Facile discovery of surrogate cytokine agonists

Author: Michelle Yen, Junming Ren, Qingxiang Liu, Caleb R. Glassman, Timothy P. Sheahan, Lora K. Picton, Fernando R. Moreira, Arjun Rustagi, Kevin M. Jude, Xiang Zhao, Catherine A. Blish, Ralph S. Baric, Leon L. Su, K. Christopher Garcia

Issue&Volume: 2022-03-23

Abstract: Cytokines are powerful immune modulators that initiate signaling through receptordimerization, but natural cytokines have structural limitations as therapeutics. Wepresent a strategy to discover cytokine surrogate agonists by using modular ligandsthat exploit induced proximity and receptor dimer geometry as pharmacological metricsamenable to high-throughput screening. Using VHH and scFv to human interleukin-2/15,type-I interferon, and interleukin-10 receptors, we generated combinatorial matricesof single-chain bispecific ligands that exhibited diverse spectrums of functionalactivities, including potent inhibition of SARS-CoV-2 by surrogate interferons. Crystalstructures of IL-2R:VHH complexes revealed that variation in receptor dimer geometriesresulted in functionally diverse signaling outputs. This modular platform enabledengineering of surrogate ligands that compelled assembly of an IL-2R/IL-10R heterodimer,which does not naturally exist, that signaled through pSTAT5 on T and natural killer(NK) cells. This “cytokine med-chem” approach, rooted in principles of induced proximity,is generalizable for discovery of diversified agonists for many ligand-receptor systems.

DOI: 10.1016/j.cell.2022.02.025

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00247-1