Citation: Lilin Song, Mengru Sun, Yuqing Song, Feng Zhang, Bei Zhao, Hairong Zeng, Jinhui Shi, Huixin Liu, Shanshan Zhao, Tian Tian, Heng Yin, Guangbo Ge. Rationally engineered IR-783 octanoate as an enzyme-activatable fluorogenic tool for functional imaging of hNotum in living systems[J]. Chinese Chemical Letters, ;2024, 35(11): 109601. doi: 10.1016/j.cclet.2024.109601 shu

Rationally engineered IR-783 octanoate as an enzyme-activatable fluorogenic tool for functional imaging of hNotum in living systems

Lilin Song ^{a, c, 1} ,
Mengru Sun ^{b, 1} ,
Yuqing Song ^b ,
Feng Zhang ^b ,
Bei Zhao ^b ,
Hairong Zeng ^b ,
Jinhui Shi ^b ,
Huixin Liu ^d ,
Shanshan Zhao ^e ,
Tian Tian ^{b, *,} ,
Heng Yin ^{a, c} ,
Guangbo Ge ^{b, *,}

a.
Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
b.
Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Re-search, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
c.
University of Chinese Academy of Sciences, Beijing 100049, China
d.
Health Sciences Institute, China Medical University, Shenyang 110122, China
e.
Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, China

tiantian@shutcm.edu.cn

geguangbo@shutcm.edu.cn

Received Date: 24 October 2023
Revised Date: 29 January 2024
Accepted Date: 30 January 2024
Available Online: 4 February 2024

Figures(4)

As a vital negative regulator of Wnt signaling pathway, human Notum (hNotum) plays a crucial regulatory role in the progression of many human diseases. Deciphering the relevance of hNotum to human diseases requires practical and reliable tools for visualizing hNotum activity in living systems. Herein, an enzyme-activatable fluorogenic tool (IR-783 octanoate) was rationally engineered for sensing and imaging hNotum activity in living systems by integrating computer-aided molecular design and biochemical assays. IR-783 octanoate showed good optical properties, excellent specificity and high binding-affinity towards hNotum (K_m = 0.98 µmol/L). IR-783 octanoate could be well up-taken into the cancerous cells or tumors that over-expressed organic anion transporting polypeptides (OATPs), and then hydrolyzed by cellular hNotum to release free IR-783 ketone, which created brightly fluorescent signals around 646 nm. Further investigations showed that IR-783 octanoate achieved a good performance for in-situ functional imaging of hNotum in both living cells, cancerous tissues and organs. It was also found that some SW620 cells with multipolar spindles could be stained by IR-783 octanoate to emit extremely bright signals, suggesting that this agent could be used as a novel visualizing tool for tracing the cells undergoing abnormal cell mitoses. Collectively, this study devises a highly specific fluorogenic tool for in-situ functional imaging of hNotum in living systems, which offers a practical and reliable tool to dynamically track the changes in hNotum activity under various conditions.
- hNotum,
- Optical substrate,
- Computer-aided molecular design,
- In-situ functional imaging,
- Cancer diagnosis
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