Wang Tianlu, Liu Siyao, Ke Yuepeng, Ali Sher, Wang Rui, Hong Tingting, Liu Ziying, Ma Guolin, Lan Tien-Hung, Wang Fen, Zhu Michael X, Huang Yun, Zhou Yubin
Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA.
Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA.
Nat Chem Biol. 2025 Jun 13. doi: 10.1038/s41589-025-01918-z.
Chemically induced proximity (CIP) has remarkably advanced the development of molecular and cellular therapeutics. To maximize therapeutic potential, there is a pressing need to expand the repertoire of CIP systems of translational values, favoring chemical ligands that are cost-effective, structurally simple, biocompatible, reversible and have minimal side effects. Here, we present a salicylic acid (SA)-mediated binary association system (SAMBA), evolved from a tobacco SA receptor, that enables rapid protein-protein heterodimerization in response to SA or aspirin after hydrolysis. We demonstrate the broad applicability of SAMBA in various biological contexts, including SA-dependent reprogramming of a protein-based reaction-diffusion system, graded gating of calcium channels, inducible initiation of receptor tyrosine kinase-mediated signaling and gene expression, and tunable activation of chimeric antigen receptor T cells. Our work establishes SAMBA as a versatile chemogenetic platform that allows temporal control of biological processes and therapeutic cells both in vitro and in vivo.
化学诱导邻近效应（CIP）极大地推动了分子和细胞疗法的发展。为了使治疗潜力最大化，迫切需要扩大具有转化价值的CIP系统，青睐那些具有成本效益、结构简单、生物相容性好、可逆且副作用最小的化学配体。在此，我们展示了一种由烟草水杨酸（SA）受体进化而来的水杨酸（SA）介导的二元缔合系统（SAMBA），该系统能够在SA或阿司匹林水解后快速实现蛋白质-蛋白质异源二聚化。我们证明了SAMBA在各种生物学环境中的广泛适用性，包括基于蛋白质的反应-扩散系统的SA依赖性重编程、钙通道的分级门控、受体酪氨酸激酶介导的信号传导和基因表达的诱导起始，以及嵌合抗原受体T细胞的可调激活。我们的工作将SAMBA确立为一个多功能的化学遗传学平台，可在体外和体内对生物过程和治疗性细胞进行时间控制。
