利用編碼文庫發(fā)現(xiàn)活細(xì)胞膜蛋白激動(dòng)劑

作者：小柯機(jī)器人 發(fā)布時(shí)間：2024/8/25 18:43:50

本期文章：《美國化學(xué)會(huì)志》：Online/在線發(fā)表

香港大學(xué)李笑宇團(tuán)隊(duì)報(bào)道了利用編碼文庫發(fā)現(xiàn)活細(xì)胞膜蛋白激動(dòng)劑。相關(guān)研究成果發(fā)表在2024年8月22日出版的《美國化學(xué)會(huì)雜志》。

識(shí)別膜蛋白的生物活性配體是化學(xué)生物學(xué)中的一項(xiàng)重要任務(wù)。

該文中，研究人員報(bào)告了一種通過選擇活細(xì)胞上的DNA編碼文庫（DEL）直接鑒定針對膜蛋白的小分子激動(dòng)劑的方法。這種方法將細(xì)胞外配體結(jié)合與細(xì)胞內(nèi)生化轉(zhuǎn)化聯(lián)系起來，從而將選擇偏向于激動(dòng)劑鑒定。研究人員用三種膜蛋白證明了該方法：表皮生長因子受體（EGFR）、血小板生成素受體（TPOR）和胰島素受體（INSR）。

針對這些靶點(diǎn)選擇了約3000萬個(gè)和10.33億個(gè)化合物DEL，并發(fā)現(xiàn)了具有亞納米親和力和低微摩爾細(xì)胞活性的新型激動(dòng)劑。INSR激動(dòng)劑可能通過與變構(gòu)位點(diǎn)結(jié)合來激活受體，與胰島素表現(xiàn)出明顯的協(xié)同作用，并激活下游信號(hào)通路。值得注意的是，激動(dòng)劑沒有激活胰島素樣生長因子1受體（IGF-1R），這是一種高度同源的受體，其激活可能導(dǎo)致腫瘤進(jìn)展。

總的來說，該項(xiàng)工作開發(fā)了一種在細(xì)胞表面進(jìn)行“功能性”DEL選擇的方法，并可能為膜蛋白激動(dòng)劑的發(fā)現(xiàn)提供一種廣泛適用的方法。

附：英文原文

Title: Agonist Discovery for Membrane Proteins on Live Cells by Using DNA-encoded Libraries

Author: Yiran Huang, Rui Hou, Fong Sang Lam, Yunxuan Jia, Yu Zhou, Xun He, Gang Li, Feng Xiong, Yan Cao, Dongyao Wang, Xiaoyu Li

Issue&Volume: August 22, 2024

Abstract: Identifying biologically active ligands for membrane proteins is an important task in chemical biology. We report an approach to directly identify small molecule agonists against membrane proteins by selecting DNA-encoded libraries (DELs) on live cells. This method connects extracellular ligand binding with intracellular biochemical transformation, thereby biasing the selection toward agonist identification. We have demonstrated the methodology with three membrane proteins: epidermal growth factor receptor (EGFR), thrombopoietin receptor (TPOR), and insulin receptor (INSR). A ～30 million and a 1.033 billion-compound DEL were selected against these targets, and novel agonists with subnanomolar affinity and low micromolar cellular activities have been discovered. The INSR agonists activated the receptor by possibly binding to an allosteric site, exhibited clear synergistic effects with insulin, and activated the downstream signaling pathways. Notably, the agonists did not activate the insulin-like growth factor 1 receptor (IGF-1R), a highly homologous receptor whose activation may lead to tumor progression. Collectively, this work has developed an approach toward “functional” DEL selections on the cell surface and may provide a widely applicable method for agonist discovery for membrane proteins.

DOI: 10.1021/jacs.4c08624

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c08624

期刊信息

JACS：《美國化學(xué)會(huì)志》，創(chuàng)刊于1879年。隸屬于美國化學(xué)會(huì)，最新IF：16.383

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