Bérenger Sophie, Adamska Justyna M, Deflorian Francesca, de Graaf Chris, Palmer Christie B, Szpakowska Martyna, Chevigné Andy, de Esch Iwan J P, Zarzycka Barbara, Vischer Henry F, Wijtmans Maikel, Leurs Rob
Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
Nxera Pharma, Steinmetz Building, Granta Park, Great Abington, Cambridge CB21 6DG, U.K.
ACS Omega. 2025 Feb 18;10(8):8675-8686. doi: 10.1021/acsomega.4c11583. eCollection 2025 Mar 4.
Photopharmacology offers the promise of optical modulation of cellular signaling in a spatially and temporally controlled fashion with light-sensitive molecules. This study presents the first small-molecule photoswitchable agonist for an atypical G protein-coupled receptor (GPCR), the atypical chemokine receptor 3 (ACKR3). Inspired by a known benzylpiperidine-based ACKR3 agonist scaffold, 12 photoswitchable azobenzene-containing analogs were synthesized and characterized for their interaction with ACKR3. After analysis of concise Structure-Photochemistry and Structure-Affinity Relationships (SAR), compound was selected as the best photoswitchable ACKR3 agonist in the series. Compound can be effectively switched from its thermodynamically stable state to the less active -isomer with a photostationary state of 96%. The thermodynamically less stable only slowly switches back to the state ( ∼ 15 days), and - binds and activates ACKR3 at 10-fold lower concentrations compared to its -isomer. Compound demonstrates selectivity for ACKR3 within in a wide panel of chemokine receptors. Using the recently published ACKR3 cryo-EM structures in computational studies, a binding mode for - is proposed that is perfectly in line with the observed SAR and the reduction in interaction with ACKR3 upon photoswitching. ACKR3 agonist (VUF25471) is the first photoswitchable ligand for an atypical GPCR and will be a useful tool to investigate the role of ACKR3 in biological settings.
光药理学有望利用光敏分子以空间和时间可控的方式对细胞信号进行光学调制。本研究展示了首个用于非典型G蛋白偶联受体（GPCR）——非典型趋化因子受体3（ACKR3）的小分子光开关激动剂。受已知的基于苄基哌啶的ACKR3激动剂支架启发，合成了12种含光开关偶氮苯的类似物，并对其与ACKR3的相互作用进行了表征。在分析了简洁的结构-光化学和结构-亲和力关系（SAR）后，化合物被选为该系列中最佳的光开关ACKR3激动剂。化合物可以有效地从其热力学稳定的状态转变为活性较低的 -异构体，光稳态为96%。热力学上较不稳定的 仅缓慢地变回 状态（半衰期约为15天），并且 -异构体与ACKR3结合并激活时的浓度比其 -异构体低10倍。化合物在广泛的趋化因子受体中表现出对ACKR3的选择性。在计算研究中使用最近公布的ACKR3冷冻电镜结构，提出了 -异构体的结合模式，这与观察到的SAR以及光开关后与ACKR3相互作用的降低完全一致。ACKR3激动剂 （VUF25471）是首个用于非典型GPCR的光开关配体，将成为研究ACKR3在生物环境中作用的有用工具。
