美国斯坦福大学Alice Ting团队近期取得重要工作进展，他们开发了用于可编程感知和控制细胞行为的合成GPCR。相关研究成果2024年12月4日在线发表于《自然》杂志上。

据介绍，介导抗原依赖性细胞反应的合成受体正在改变治疗、药物发现和基础研究。然而，嵌合抗原受体等成熟技术只能检测固定化抗原，输出范围有限，缺乏内置药物控制。

研究人员设计了合成的G蛋白偶联受体（GPCR），能够驱动各种天然或非天然细胞过程，以响应用户定义的抗原。研究人员通过在GPCR支架上设计和融合条件自抑制结构域来实现模块化抗原门控。抗原与融合的纳米体结合可以缓解自身抑制，并使受体能够被药物激活，从而产生可编程的抗原门控G蛋白偶联工程受体（PAGER）。

研究人员从相应的纳米体粘合剂中一步创建了对十几种生物和治疗上重要的可溶性和细胞表面抗原有反应的PAGER。不同的PAGER支架允许抗原结合来驱动转基因表达、实时荧光或内源性G蛋白激活，从而能够控制不同的细胞功能。

研究人员展示了PAGER的多种应用，包括诱导T细胞沿可溶性抗原梯度迁移、控制巨噬细胞分化、分泌治疗性抗体和抑制小鼠脑切片中的神经元活动。由于其模块化设计和通用性，PAGER工具在发现和转化科学中将具有广泛的用途。

附：英文原文

Title: Synthetic GPCRs for programmable sensing and control of cell behaviour

Author: Kalogriopoulos, Nicholas A., Tei, Reika, Yan, Yuqi, Klein, Peter M., Ravalin, Matthew, Cai, Bo, Soltesz, Ivan, Li, Yulong, Ting, Alice

Issue&Volume: 2024-12-04

Abstract: Synthetic receptors that mediate antigen-dependent cell responses are transforming therapeutics, drug discovery and basic research1,2. However, established technologies such as chimeric antigen receptors3 can only detect immobilized antigens, have limited output scope and lack built-in drug control3,4,5,6,7. Here we engineer synthetic G-protein-coupled receptors (GPCRs) that are capable of driving a wide range of native or non-native cellular processes in response to a user-defined antigen. We achieve modular antigen gating by engineering and fusing a conditional auto-inhibitory domain onto GPCR scaffolds. Antigen binding to a fused nanobody relieves auto-inhibition and enables receptor activation by drug, thus generating programmable antigen-gated G-protein-coupled engineered receptors (PAGERs). We create PAGERs that are responsive to more than a dozen biologically and therapeutically important soluble and cell-surface antigens in a single step from corresponding nanobody binders. Different PAGER scaffolds allow antigen binding to drive transgene expression, real-time fluorescence or endogenous G-protein activation, enabling control of diverse cellular functions. We demonstrate multiple applications of PAGER, including induction of T cell migration along a soluble antigen gradient, control of macrophage differentiation, secretion of therapeutic antibodies and inhibition of neuronal activity in mouse brain slices. Owing to its modular design and generalizability, we expect PAGERs to have broad utility in discovery and translational science.

DOI: 10.1038/s41586-024-08282-3

Source: https://www.nature.com/articles/s41586-024-08282-3