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构象锁定抗体可用于KRAS抑制剂的发现和表征
作者:小柯机器人 发布时间:2022/1/9 14:04:45

近日,美国基因泰克公司Marie Evangelista等研究人员合作发现,构象锁定抗体可用于KRAS抑制剂的发现和表征。相关论文于2022年1月6日在线发表于国际学术期刊《自然—生物技术》。

研究人员表示,稳定非活性蛋白构象的小分子是一种未被充分利用的策略,用于对动态或其他难以解决的蛋白进行药物治疗。

为了促进这种抑制剂的发现和表征,研究人员创建了一个筛选平台,以确定分子探针的构象锁定抗体(CLAMP),从而区分和诱导罕见的蛋白质构象状态。将该方法应用于KRAS,研究人员发现CLAMP能识别由共价抑制剂稳定的KRASG12C的开放构象。

其中一个CLAMP能够使KRASG12C的共价修饰在体内可视化,并可用于研究患者肿瘤中对KRASG12C抑制剂的反应异质性。第二个CLAMP通过稳定KRASG12C的特定构象,增强了与KRASG12C开关II区(SWII)结合的弱配体的亲和力,从而能够在高通量筛选中发现可作为药物开发线索的此类配体。结果表明,结合抗体和小分子的互补特性将有利于动态蛋白质的研究和药物治疗。

附:英文原文

Title: Conformation-locking antibodies for the discovery and characterization of KRAS inhibitors

Author: Davies, Christopher W., Oh, Angela J., Mroue, Rana, Steffek, Micah, Bruning, John M., Xiao, Yang, Feng, Siyu, Jayakar, Sangeeta, Chan, Emily, Arumugam, Vidhyalakshmi, Uribe, Sean Carlo, Drummond, Jake, Frommlet, Alexandra, Lu, Cheng, Franke, Yvonne, Merchant, Mark, Koeppen, Hartmut, Quinn, John G., Malhotra, Sushant, Do, Steve, Gazzard, Lewis, Purkey, Hans E., Rudolph, Joachim, Mulvihill, Melinda M., Koerber, James T., Wang, Weiru, Evangelista, Marie

Issue&Volume: 2022-01-06

Abstract: Small molecules that stabilize inactive protein conformations are an underutilized strategy for drugging dynamic or otherwise intractable proteins. To facilitate the discovery and characterization of such inhibitors, we created a screening platform to identify conformation-locking antibodies for molecular probes (CLAMPs) that distinguish and induce rare protein conformational states. Applying the approach to KRAS, we discovered CLAMPs that recognize the open conformation of KRASG12C stabilized by covalent inhibitors. One CLAMP enables the visualization of KRASG12C covalent modification in vivo and can be used to investigate response heterogeneity to KRASG12C inhibitors in patient tumors. A second CLAMP enhances the affinity of weak ligands binding to the KRASG12C switchII region (SWII) by stabilizing a specific conformation of KRASG12C, thereby enabling the discovery of such ligands that could serve as leads for the development of drugs in a high-throughput screen. We show that combining the complementary properties of antibodies and small molecules facilitates the study and drugging of dynamic proteins.

DOI: 10.1038/s41587-021-01126-9

Source: https://www.nature.com/articles/s41587-021-01126-9

期刊信息

Nature Biotechnology:《自然—生物技术》,创刊于1996年。隶属于施普林格·自然出版集团,最新IF:31.864
官方网址:https://www.nature.com/nbt/
投稿链接:https://mts-nbt.nature.com/cgi-bin/main.plex