浙江大学张岩等研究人员合作开发出基于结构设计的非肥大性爱帕琳肽受体调节剂。这一研究成果于2024年2月29日在线发表在国际学术期刊《细胞》上。
研究人员报告了爱帕琳肽受体（APLNR）-Gi1复合物与三种具有不同信号特征的激动剂结合后的冷冻电镜（cryo-EM）结构。结合功能测试，研究人员发现APLNR中的“孪生热点”是决定信号传导偏向的关键因素，从而指导研究人员合理设计了两种专属G蛋白偏向的激动剂WN353和WN561。WN353和WN561刺激APLNR-G蛋白复合物的cryo-EM结构进一步证实了所设计的配体采用了所需的姿势。
病理生理学实验证明，与已有的APLNR激动剂相比，WN561对心肌肥厚有更好的治疗效果，并能减少不良反应。总之，研究人员设计的APLNR调节剂可促进下一代心血管药物的开发。
据悉，爱帕琳肽是心血管稳态中的一种关键激素，它能激活APLNR，而该受体被认为是治疗心血管疾病的一个很有前景的靶点。然而，通过β-抑制蛋白途径产生的不良反应限制了其药理应用。
附：英文原文
Title: Structure-based design of non-hypertrophic apelin receptor modulator
Author: Wei-Wei Wang, Su-Yu Ji, Wenjia Zhang, Junxia Zhang, Chenxi Cai, Rubi Hu, Shao-Kun Zang, Luwei Miao, Haomang Xu, Li-Nan Chen, Zongkuai Yang, Jia Guo, Jiao Qin, Dan-Dan Shen, Ping Liang, Yan Zhang, Yan Zhang
Issue&Volume: 2024-02-29
Abstract: Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor(APLNR), which is regarded as a promising therapeutic target for cardiovascular disease.However, adverse effects through the β-arrestin pathway limit its pharmacologicaluse. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles. Combined withfunctional assays, we have identified “twin hotspots” in APLNR as key determinantsfor signaling bias, guiding the rational design of two exclusive G-protein-biasedagonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-Gprotein complexes further confirm that the designed ligands adopt the desired poses.Pathophysiological experiments have provided evidence that WN561 demonstrates superiortherapeutic effects against cardiac hypertrophy and reduced adverse effects comparedwith the established APLNR agonists. In summary, our designed APLNR modulator mayfacilitate the development of next-generation cardiovascular medications.
DOI: 10.1016/j.cell.2024.02.004
Source: https://www.cell.com/cell/abstract/S0092-8674(24)00125-9