A Practical and High-Affinity Fluorescent Probe for Uridine Diphosphate Glucuronosyltransferase 1A1: A Good Surrogate for Bilirubin,Journal of Medicinal Chemistry

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A Practical and High-Affinity Fluorescent Probe for Uridine Diphosphate Glucuronosyltransferase 1A1: A Good Surrogate for Bilirubin
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-11-20 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01097
Xia Lv _{1,

2,

3} , Lei Feng _{4,

5} , Chun-Zhi Ai ₃ , Jie Hou _{4,

5} , Ping Wang _{1,

3} , Li-Wei Zou _{1,

3} , Jie Cheng ₆ , Guang-Bo Ge _{1,

3} , Jing-Nan Cui ₅ , Ling Yang ₁

Affiliation

This study aimed to develop a practical and high-affinity fluorescent probe for uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), a key conjugative enzyme responsible for the elimination and detoxification of many potentially harmful compounds. Several substrates derived from N-butyl-4-phenyl-1,8-naphthalimide were designed and synthesized on the basis of the substrate preference of UGT1A1 and the principle of photoinduced electron transfer (PET). Following the preliminary screening, substrate 2 was found with a high specificity and high affinity toward UGT1A1, while such biotransformation brought remarkable changes in fluorescence emission. Both inhibition kinetic analyses and molecular docking simulations demonstrated that 2 could bind on UGT1A1 at the same ligand-binding site as bilirubin. Furthermore, this newly developed probe was successfully used for sensing UGT1A1 activities and the high-throughput screening of UGT1A1 modulators in complex biological samples. In conclusion, a practical and high-affinity fluorescent probe for UGT1A1 was designed and well-characterized, which could serve as a good surrogate for bilirubin to investigate UGT1A1-ligand interactions.

中文翻译：

实用和高亲和力的尿苷二磷酸葡萄糖醛糖苷基转移酶1A1荧光探针：胆红素的良好替代品

这项研究旨在为尿苷二磷酸葡萄糖醛酸糖基转移酶1A1（UGT1A1）开发一种实用且高亲和力的荧光探针，这是一种关键的结合酶，负责消除和清除许多潜在有害的化合物。基于UGT1A1的底物偏好和光致电子转移（PET）原理，设计合成了几种N-丁基-4-苯基-1，8-萘二甲酰亚胺衍生的底物。经过初步筛选，发现底物2对UGT1A1具有高特异性和高亲和力，而这种生物转化带来了荧光发射方面的显着变化。抑制动力学分析和分子对接模拟均表明2可以在与胆红素相同的配体结合位点上结合在UGT1A1上。此外，这种新开发的探针已成功用于传感UGT1A1活性和复杂生物样品中UGT1A1调节剂的高通量筛选。总之，已设计并表征了实用且高亲和力的UGT1A1荧光探针，可作为研究胆红素的良好替代品，以研究UGT1A1-配体之间的相互作用。

更新日期：2017-11-21

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