德国慕尼黑工业大学Bernhard Kuster课题组取得一项新突破。他们的研究利用剂量分辨表达蛋白质组学揭示出细胞药物表型的分子基础。2024年5月7日，国际学术期刊《自然-生物技术》发表了这一成果。

研究人员介绍一种全蛋白质组方法decryptE，它能测量药物诱导蛋白质表达变化的全部剂量反应特征，为细胞药物作用机制提供信息。对144种临床药物和8,000种研究化合物蛋白质进行化验，得出了100多万条剂量反应曲线，这些曲线可以在蛋白质组学数据库和Shiny定制应用程序中进行在线交互式验证。对这些集合数据的分析为已知的表型药物效应提供了分子解释，并揭示了人类药物作用的新机制。

研究人员发现组蛋白去乙酰化酶抑制剂能显著下调T细胞受体复合物，在体外和体内导致人T细胞活化受损。这为组蛋白去乙酰化酶抑制剂在某些淋巴瘤和自身免疫性疾病中的疗效提供了合理的解释，同时也解释了它们在治疗实体瘤方面表现不佳的原因。

附：英文原文

Title: Decrypting the molecular basis of cellular drug phenotypes by dose-resolved expression proteomics

Author: Eckert, Stephan, Berner, Nicola, Kramer, Karl, Schneider, Annika, Mller, Julian, Lechner, Severin, Brajkovic, Sarah, Sakhteman, Amirhossein, Graetz, Christian, Fackler, Jonas, Dudek, Michael, Pfaffl, Michael W., Knolle, Percy, Wilhelm, Stephanie, Kuster, Bernhard

Issue&Volume: 2024-05-07

Abstract: Proteomics is making important contributions to drug discovery, from target deconvolution to mechanism of action (MoA) elucidation and the identification of biomarkers of drug response. Here we introduce decryptE, a proteome-wide approach that measures the full dose–response characteristics of drug-induced protein expression changes that informs cellular drug MoA. Assaying 144 clinical drugs and research compounds against 8,000 proteins resulted in more than 1million dose–response curves that can be interactively explored online in ProteomicsDB and a custom-built Shiny App. Analysis of the collective data provided molecular explanations for known phenotypic drug effects and uncovered new aspects of the MoA of human medicines. We found that histone deacetylase inhibitors potently and strongly down-regulated the T cell receptor complex resulting in impaired human T cell activation in vitro and ex vivo. This offers a rational explanation for the efficacy of histone deacetylase inhibitors in certain lymphomas and autoimmune diseases and explains their poor performance in treating solid tumors.

DOI: 10.1038/s41587-024-02218-y

Source: https://www.nature.com/articles/s41587-024-02218-y