美国北卡罗来纳大学Bryan L. Roth等研究人员合作完成外围受限化学发生系统的结构导向设计。2024年12月3日，《细胞》杂志在线发表了这一最新研究成果。

据研究人员介绍，设计者受体仅由设计者药物激活（DREADD），是用于远程控制细胞信号传导、神经活动、行为和生理过程的化学遗传工具。

通过结构引导的方法，研究人员提供了一种外围限制的Gi-DREADD，即羟基羧酸受体DREADD（HCAD），其天然受体在大脑中的表达极少，且化学激活剂无法穿过血脑屏障（BBB）。这一成果是通过联合诱变、大规模按需合成库的类比、通过冷冻电镜（cryo-EM）确定设计的DREADD受体结构，并验证HCAD功能实现的。

HCAD在背根神经节（DRG）神经元中的表达与激活，能够抑制动作电位（AP）放电，减少急性和组织损伤引起的炎症性疼痛。HCAD化学遗传系统扩展了研究众多外围系统的可能性，同时对中枢神经系统（CNS）的不良影响极小。

用于生成HCAD的结构引导方法，还具有加速开发新兴化学遗传工具的潜力，有望推动基础和转化科学的发展。

附：英文原文

Title: Structure-guided design of a peripherally restricted chemogenetic system

Author: Hye Jin Kang, Brian E. Krumm, Adrien Tassou, Matan Geron, Jeffrey F. DiBerto, Nicholas J. Kapolka, Ryan H. Gumpper, Kensuke Sakamoto, D. Dewran Kocak, Reid H.J. Olsen, Xi-Ping Huang, Shicheng Zhang, Karen L. Huang, Saheem A. Zaidi, MyV.T. Nguyen, Min Jeong Jo, Vsevolod Katritch, Jonathan F. Fay, Grégory Scherrer, Bryan L. Roth

Issue&Volume: 2024-12-03

Abstract: Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remotely controlling cellular signaling, neural activity, behavior, and physiology. Using a structure-guided approach, we provide a peripherally restricted Gi-DREADD, hydroxycarboxylic acid receptor DREADD (HCAD), whose native receptor is minimally expressed in the brain, and a chemical actuator that does not cross the blood-brain barrier (BBB). This was accomplished by combined mutagenesis, analoging via an ultra-large make-on-demand library, structural determination of the designed DREADD receptor via cryoelectron microscopy (cryo-EM), and validation of HCAD function. Expression and activation of HCAD in dorsal root ganglion (DRG) neurons inhibit action potential (AP) firing and reduce both acute and tissue-injury-induced inflammatory pain. The HCAD chemogenetic system expands the possibilities for studying numerous peripheral systems with little adverse effects on the central nervous system (CNS). The structure-guided approach used to generate HCAD also has the potential to accelerate the development of emerging chemogenetic tools for basic and translational sciences.

DOI: 10.1016/j.cell.2024.11.001

Source: https://www.cell.com/cell/abstract/S0092-8674(24)01275-3