A facile turn-on chemiluminescence probe for sensitive imaging on aminopeptidase N activity,Luminescence

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A facile turn-on chemiluminescence probe for sensitive imaging on aminopeptidase N activity
Luminescence ( IF 3.2 ) Pub Date : 2022-06-07 , DOI: 10.1002/bio.4302
Ru Sun ₁ , Xuesong Wu ₂ , Yanjia Mao ₂ , Hongbo Wang ₂ , Chong Bian ₃ , Panpan Lv ₃ , Zhen Zhao ₃ , Xinwei Li ₁ , Wei Fu ₁ , Jianzhong Lu ₁ , Zhijuan Cao ₁

Affiliation

Aminopeptidase N, as a target for drug discovery, shows marked relationships with many diseases, especially liver injury and cancer. Here, we explored a chemiluminescence (CL) probe for sensing APN by tethering the APN-specific substrate group to the ortho-acrylated phenoxy-dioxetane scaffold. In this way, two CL probes (APN-CL and BAPN-CL) were designed with noncapped leucine and butoxy-carbonyl capped leucine as the protecting group to preserve the chemiexcitation energy. The uncovered leucine was demonstrated to be essential for detection of APN activity by comparing the CL intensity of two CL probes. Probe APN-CL was turned on upon APN cleavage, resulting in a high chemiluminescent emission, whereas the chemiexcitation energy of probe BAPN-CL was still restrained even with the high-level APN. The result was further elucidated by molecular docking simulations. Probe APN-CL exhibited a fast response and high sensitivity with a detection limit of 0.068 U/L, and an excellent specificity for the discrimination of APN from biological ions, small molecules, and other proteases commonly found in living system. By virtue of good stability and cell viability, probe APN-CL imaged abnormal levels of APN in tumour cells and tumour-bearing mice. Moreover, this probe APN-CL could be easily used to evaluate APN inhibitors and APN levels in plasma samples from 20 patients. Overall, as a facile and cost-effective probe, APN-CL will be a promising alternative in the early diagnosis of pathologies and for cost-effective screening of inhibitors.

中文翻译：

一种用于氨肽酶 N 活性敏感成像的简便开启化学发光探针

氨基肽酶 N 作为药物发现的靶点，与许多疾病，尤其是肝损伤和癌症有显着的关系。在这里，我们探索了一种化学发光 (CL) 探针，通过将 APN 特异性底物基团连接到正丙烯酸酯化苯氧基-二氧杂环丁烷支架上来检测 APN。通过这种方式，设计了两种 CL 探针（APN-CL和BAPN-CL），以非封端的亮氨酸和丁氧基羰基封端的亮氨酸作为保护基团来保持化学激发能。通过比较两个 CL 探针的 CL 强度，证明未发现的亮氨酸对于检测 APN 活性至关重要。探针APN - CL在 APN 裂解时打开，导致高化学发光发射，而即使使用高水平 APN ，探针BAPN-CL的化学激发能仍然受到限制。通过分子对接模拟进一步阐明了结果。Probe APN - CL反应速度快，灵敏度高，检出限为0.068 U/L，对区分APN与生物离子、小分子和其他生命系统中常见的蛋白酶有很好的特异性。凭借良好的稳定性和细胞活力，探针APN - CL对肿瘤细胞和荷瘤小鼠中异常水平的 APN 进行成像。此外，该探针APN-CL可以很容易地用于评估来自 20 名患者的血浆样本中的 APN 抑制剂和 APN 水平。总体而言，作为一种简便且具有成本效益的探针，APN - CL将成为早期病理诊断和具有成本效益的抑制剂筛选的有希望的替代方案。

更新日期：2022-06-07

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