School of Chemistry and Biochemistry, National Centre of Competence in Research (NCCR) Chemical Biology, University of Geneva , CH-1211 Geneva, Switzerland.
J Am Chem Soc. 2017 Jan 11;139(1):231-238. doi: 10.1021/jacs.6b09643. Epub 2016 Dec 21.
In this study, we demonstrate that appendage of a single asparagusic acid residue (AspA tag) is sufficient to ensure efficient cellular uptake and intracellular distribution of fully unprotected peptides. We apply this new delivery method to induce apoptotic response in cancer cells using long (up to 20mer) BH3 domain peptides. Moreover, to understand the molecular mechanism of the cellular uptake, we perform chemical proteomics experiments and identify the direct molecular targets of the asparagusic acid tag. Our findings document covalent bond formation between the asparagusic acid moiety and the cysteines 556 and 558 on the surface of the transferrin receptor resulting in subsequent endocytic uptake of the payload. We believe that the small size, low cellular toxicity and the efficient transferrin receptor-mediated uptake render the AspA tag highly attractive for various life science applications.
在这项研究中，我们证明了添加一个天门冬氨酸残基（AspA 标签）足以确保完全未保护的肽的有效细胞摄取和细胞内分布。我们将这种新的递药方法应用于使用长（长达 20 个残基）BH3 结构域肽诱导癌细胞的凋亡反应。此外，为了了解细胞摄取的分子机制，我们进行了化学蛋白质组学实验，并鉴定了天门冬氨酸标签的直接分子靶标。我们的研究结果记录了天门冬氨酸部分与转铁蛋白受体表面上的半胱氨酸 556 和 558 之间形成共价键，从而导致随后的内吞摄取有效载荷。我们相信，其尺寸小、细胞毒性低且转铁蛋白受体介导的摄取效率高，使得 AspA 标签在各种生命科学应用中极具吸引力。
