小柯机器人

通过热位移分析可鉴定组织和全血中的药物靶标
2020-01-25 10:57

德国葛兰素史克公司Giovanna Bergamini、Marcus Bantscheff、欧洲生物学实验室Mikhail M. Savitski等研究人员合作通过热位移分析鉴定了组织和全血中的药物靶标。这一研究成果2020年1月20日在线发表在国际学术期刊《自然—生物技术》上。

研究人员报道了组织热蛋白质组分析(tissue-TPP)技术,它通过使用定量质谱检测蛋白质热稳定性的变化来测量小分子药物与药物治疗动物组织样品中蛋白质的结合。研究人员报告了器官特异性、蛋白质组范围的热稳定性图,并得出了大鼠肝、肺、肾和脾中非共价组蛋白去乙酰化酶抑制剂panobinostat和小鼠睾丸中B-Raf抑制剂vemurafenib的靶标概况。此外,研究人员设计了血液CETSA和血液TPP,并将其用于直接测量全血中panobinostat和BET家族抑制剂JQ1的靶向和脱靶情况。panobinostat的血液TPP分析证实了其与已知靶标的结合,还揭示了锌指转录因子ZNF512的热稳定性。这些方法将有助于阐明体内药物作用的机制。

据介绍,对于简单的细胞系统,科学家已经建立了使用诸如细胞热位移测定法(CETSA)之类的方法来监测药物-靶标相互作用的方法,但在体内仍然具有挑战性。

附:英文原文

Title: Identifying drug targets in tissues and whole blood with thermal-shift profiling

Author: Jessica Perrin, Thilo Werner, Nils Kurzawa, Anna Rutkowska, Dorothee D. Childs, Mathias Kalxdorf, Daniel Poeckel, Eugenia Stonehouse, Katrin Strohmer, Bianca Heller, Douglas W. Thomson, Jana Krause, Isabelle Becher, H. Christian Eberl, Johanna Vappiani, Daniel C. Sevin, Christina E. Rau, Holger Franken, Wolfgang Huber, Maria Faelth-Savitski, Mikhail M. Savitski, Marcus Bantscheff, Giovanna Bergamini

Issue&Volume: 2020-01-20

Abstract: Monitoring drug–target interactions with methods such as the cellular thermal-shift assay (CETSA) is well established for simple cell systems but remains challenging in vivo. Here we introduce tissue thermal proteome profiling (tissue-TPP), which measures binding of small-molecule drugs to proteins in tissue samples from drug-treated animals by detecting changes in protein thermal stability using quantitative mass spectrometry. We report organ-specific, proteome-wide thermal stability maps and derive target profiles of the non-covalent histone deacetylase inhibitor panobinostat in rat liver, lung, kidney and spleen and of the B-Raf inhibitor vemurafenib in mouse testis. In addition, we devised blood-CETSA and blood-TPP and applied it to measure target and off-target engagement of panobinostat and the BET family inhibitor JQ1 directly in whole blood. Blood-TPP analysis of panobinostat confirmed its binding to known targets and also revealed thermal stabilization of the zinc-finger transcription factor ZNF512. These methods will help to elucidate the mechanisms of drug action in vivo.

DOI: 10.1038/s41587-019-0388-4

Source: https://www.nature.com/articles/s41587-019-0388-4

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:68.164
官方网址:https://www.nature.com/nbt/
投稿链接:https://mts-nbt.nature.com/cgi-bin/main.plex


本期文章:《自然—生物技术》:Online/在线发表

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