Li Linlin, Wang Rongxi, He Li, Guo Hua, Fu Lei, Wang Guochang, Wang Jiarou, Chen Ziying, Peng Xingtong, Lu Xinyu, Sui Huimin, Jiang Yuanyuan, Zang Jie, Gao Lianghui, Zhu Zhaohui
Department of Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China.
Key Laboratory of Theoretical and Computational Photochemistry, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
ACS Pharmacol Transl Sci. 2024 Sep 12;7(10):3119-3130. doi: 10.1021/acsptsci.4c00316. eCollection 2024 Oct 11.
Angiotensin-converting enzyme 2 (ACE2) is not only a key to the renin-angiotensin-aldosterone system and related diseases, but also the main entry point on cell surfaces for certain coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. By analyzing the different key binding sites from the receptor-binding domain (RBD) of SARS-CoV and SARS-CoV-2, nine new ACE2-targeting peptides (A to A) were designed, synthesized and connected with a chelator, 1,4,7-triazacyclononane-'-triacetic acid (NOTA). NOTA-A, NOTA-A, NOTA-A, NOTA-A, and NOTA-A were successfully labeled with [Ga]Ga and were used for biological evaluation. [Ga]Ga-NOTA-A, [Ga]Ga-NOTA-A, and [Ga]Ga-NOTA-A showed specific binding to ACE2 via cell assays, and their binding sites and binding capacity were calculated by molecular docking and molecular dynamics simulations. In tumor-bearing mice, A549 tumors were visualized 60 min postinjection of [Ga]Ga-NOTA-A, [Ga]Ga-NOTA-A, or [Ga]Ga-NOTA-A. These peptides also accumulated in the organs with high-level ACE2 expression, confirmed by immunohistochemical stain. Among them, [Ga]Ga-NOTA-A exhibited the highest tumor uptake and tumor/background ratio, and it successfully tracked the increased ACE2 levels in mice tissues after excessive Losartan treatment. In a first-in-human study, the distribution of [Ga]Ga-NOTA-A was evaluated with positron emission tomography/computed tomography (PET/CT) in three participants without adverse events. Ga-labeled peptides originated from the coronavirus RBD, with [Ga]Ga-NOTA-A as a typical representative, seem to be safe and effective for the evaluation of ACE2 expression with PET/CT, facilitating further mechanism investigation and clinical evaluation of ACE2-related diseases.
血管紧张素转换酶2（ACE2）不仅是肾素-血管紧张素-醛固酮系统及相关疾病的关键因素，也是包括严重急性呼吸综合征冠状病毒（SARS-CoV）和SARS-CoV-2在内的某些冠状病毒在细胞表面的主要进入点。通过分析SARS-CoV和SARS-CoV-2受体结合域（RBD）的不同关键结合位点，设计、合成了9种新的靶向ACE2的肽段（A到A），并与螯合剂1,4,7-三氮杂环壬烷-N,N,N-三乙酸（NOTA）相连。NOTA-A、NOTA-A、NOTA-A、NOTA-A和NOTA-A成功用[Ga]Ga标记并用于生物学评价。通过细胞实验，[Ga]Ga-NOTA-A、[Ga]Ga-NOTA-A和[Ga]Ga-NOTA-A显示出与ACE2的特异性结合，并通过分子对接和分子动力学模拟计算了它们的结合位点和结合能力。在荷瘤小鼠中，注射[Ga]Ga-NOTA-A、[Ga]Ga-NOTA-A或[Ga]Ga-NOTA-A后60分钟可观察到A549肿瘤。免疫组化染色证实这些肽段也在ACE2高表达的器官中积累。其中，[Ga]Ga-NOTA-A表现出最高的肿瘤摄取和肿瘤/背景比值，并且成功追踪了过量氯沙坦治疗后小鼠组织中ACE2水平的升高。在一项首次人体研究中，用正电子发射断层扫描/计算机断层扫描（PET/CT）评估了[Ga]Ga-NOTA-A在三名参与者中的分布，未出现不良事件。以[Ga]Ga-NOTA-A为典型代表的源自冠状病毒RBD的Ga标记肽段，似乎对用PET/CT评估ACE2表达是安全有效的，有助于进一步开展ACE2相关疾病的机制研究和临床评估。
