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高阶蛋白质连接导致具有增强亲和力和体内稳定性的人工抗体
作者:小柯机器人 发布时间:2021/10/21 16:54:08

北京大学张文彬团队报道了高阶蛋白质连接导致具有增强亲和力和体内稳定性的人工抗体。相关研究成果发表在2021年10月19日出版的《美国化学会杂志》。

化学拓扑是蛋白质工程的一个独特维度,然而蛋白质的拓扑多样性和结构复杂性在很大程度上尚未被开发。

该文中,研究人员报告了利用源自p53dim(肿瘤抑制蛋白p53四聚体结构域的缠结同源二聚体突变体)的合理工程的交叉缠绕肽异二聚体基序合成复杂拓扑蛋白。特定位点的静电相互作用将p53dim同源二聚体基序转化为一对异质二聚体基序,具有高度特异性,可在折叠时引导链纠缠。其与分裂内肽介导的连接和/或SpyTag/SpyCatcher化学的结合有助于细胞中蛋白质杂链烷或[n]链烷的程序化合成,从而形成包含各种感兴趣蛋白质的复杂蛋白质链烷的通用和模块化方法。连接不仅增强了靶蛋白的亲和力,而且延长了其在血液中的循环时间,从而提高了体内的稳定性。

作为概念证明,已通过将人类表皮生长因子受体2-特异性附着体嵌入[n]儿茶烷支架上开发出人工抗体,并显示出比野生型附着体更高的亲和力和更好的药代动力学特征。

研究结果表明拓扑工程在治疗性蛋白质的开发中具有巨大的前景。

附:英文原文

Title: Higher Order Protein Catenation Leads to an Artificial Antibody with Enhanced Affinity and In Vivo Stability

Author: Wen-Hao Wu, Xilin Bai, Yu Shao, Chao Yang, Jingjing Wei, Wei Wei, Wen-Bin Zhang

Issue&Volume: October 19, 2021

Abstract: The chemical topology is a unique dimension for protein engineering, yet the topological diversity and architectural complexity of proteins remain largely untapped. Herein, we report the biosynthesis of complex topological proteins using a rationally engineered, cross-entwining peptide heterodimer motif derived from p53dim (an entangled homodimeric mutant of the tetramerization domain of the tumor suppressor protein p53). The incorporation of an electrostatic interaction at specific sites converts the p53dim homodimer motif into a pair of heterodimer motifs with high specificity for directing chain entanglement upon folding. Its combination with split-intein-mediated ligation and/or SpyTag/SpyCatcher chemistry facilitates the programmed synthesis of protein heterocatenane or [n]catenanes in cells, leading to a general and modular approach to complex protein catenanes containing various proteins of interest. Concatenation enhances not only the target protein’s affinity but also the in vivo stability as shown by its prolonged circulation time in blood. As a proof of concept, artificial antibodies have been developed by embedding a human epidermal growth factor receptor 2-specific affibody onto the [n]catenane scaffolds and shown to exhibit a higher affinity and a better pharmacokinetic profile than the wild-type affibody. These results suggest that topology engineering holds great promise in the development of therapeutic proteins.

DOI: 10.1021/jacs.1c06169

Source: https://pubs.acs.org/doi/10.1021/jacs.1c06169

 

期刊信息

JACS:《美国化学会志》,创刊于1879年。隶属于美国化学会,最新IF:14.612
官方网址:https://pubs.acs.org/journal/jacsat
投稿链接:https://acsparagonplus.acs.org/psweb/loginForm?code=1000