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靶向外肽酶的近红外（NIR）荧光探针的分子设计及其在检测二肽基肽酶4（DPP-4）活性中的应用。

Molecular design of near-infrared (NIR) fluorescent probes targeting exopeptidase and application for detection of dipeptidyl peptidase 4 (DPP-4) activity.

作者信息

Hoshino Yuki, Hanaoka Kenjiro, Sakamoto Kei, Yasunaga Masahiro, Kojima Takashi, Kotani Daisuke, Nomoto Ayumu, Sasaki Eita, Komatsu Toru, Ueno Tasuku, Takamaru Hiroyuki, Saito Yutaka, Seto Yasuyuki, Urano Yasuteru

机构信息

Graduate School of Pharmaceutical Sciences, The University of Tokyo 7-3-1 Hongo Bunkyo-ku Tokyo 113-0033 Japan

Graduate School of Pharmaceutical Sciences, Keio University 1-5-30 Shibakoen Minato-ku Tokyo 105-8512 Japan

出版信息

RSC Chem Biol. 2022 Mar 24;3(7):859-867. doi: 10.1039/d1cb00253h. eCollection 2022 Jul 6.

DOI:10.1039/d1cb00253h
PMID:35866167
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9257614/
Abstract

Monitoring the activities of proteases is an important requirement in biological and medical research. Near-infrared (NIR) fluorescent probes are particularly useful for fluorescence imaging, due to the high penetration of NIR and the low autofluorescence in tissue for this wavelength region, but most current NIR fluorescent probes for proteases are targeted to endopeptidase. Here, we describe a new molecular design for NIR fluorescent probes that target exopeptidase by utilizing the >110 nm blueshift of unsymmetrical Si-rhodamines upon amidation of the N atom of their xanthene moiety. Based on this molecular design, we developed Leu-SiR640 as a probe for leucine amino peptidase (LAP). Leu-SiR640 shows a one order of magnitude larger fluorescence increment (669-fold) upon reaction with LAP than existing NIR fluorescent probes. We similarly designed and synthesized EP-SiR640, a NIR fluorescent probe that targets dipeptidyl peptidase 4 (DPP-4). We show that this probe can monitor DPP-4 activity not only in living cells but also in mouse organs and tumors. This probe could also detect esophageal cancer in human clinical specimens, based on the overexpression of DPP-4 activity.

摘要

监测蛋白酶的活性是生物学和医学研究中的一项重要需求。近红外（NIR）荧光探针对于荧光成像特别有用，这是由于近红外光具有高穿透性且在该波长区域组织中的自发荧光较低，但目前大多数用于蛋白酶的近红外荧光探针都是针对内肽酶的。在此，我们描述了一种用于近红外荧光探针的新分子设计，该设计通过利用不对称硅罗丹明在其呫吨部分的N原子酰胺化时>110 nm的蓝移来靶向外肽酶。基于这种分子设计，我们开发了Leu-SiR640作为亮氨酸氨基肽酶（LAP）的探针。与现有的近红外荧光探针相比，Leu-SiR640与LAP反应时荧光增量大一个数量级（669倍）。我们同样设计并合成了EP-SiR640，一种靶向二肽基肽酶4（DPP-4）的近红外荧光探针。我们表明，该探针不仅可以监测活细胞中的DPP-4活性，还可以监测小鼠器官和肿瘤中的DPP-4活性。基于DPP-4活性的过表达，该探针还可以检测人类临床标本中的食管癌。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e279/9257614/f23fd2122a22/d1cb00253h-f8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e279/9257614/f23fd2122a22/d1cb00253h-f8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e279/9257614/4c34a3e1c01b/d1cb00253h-f4.jpg
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