由组氨酸标签配体、泛素连接酶配体和细胞穿透肽组成的三元分子对组氨酸标签蛋白进行简单有效的敲低。

Simple and efficient knockdown of His-tagged proteins by ternary molecules consisting of a His-tag ligand, a ubiquitin ligase ligand, and a cell-penetrating peptide.

作者信息

Hattori Takayuki, Okitsu Koyo, Yamazaki Norikazu, Ohoka Nobumichi, Shibata Norihito, Misawa Takashi, Kurihara Masaaki, Demizu Yosuke, Naito Mikihiko

机构信息

Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo 158-8501, Japan.

Division of Organic Chemistry, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo 158-8501, Japan.

出版信息

Bioorg Med Chem Lett. 2017 Sep 15;27(18):4478-4481. doi: 10.1016/j.bmcl.2017.08.001. Epub 2017 Aug 2.

DOI:10.1016/j.bmcl.2017.08.001

PMID:28807436

Abstract

We designed and synthesized hybrid molecules for a protein knockdown method based on the recognition of a His-tag fused to a protein of interest (POI). The synthesized target protein degradation inducers contained three functional moieties: a His-tag ligand (nickel nitrilotriacetic acid [Ni-NTA]), an E3 ligand (bestatin [BS] or MV1), and a carrier peptide (Tat or nonaarginine [R9]). The designed hybrid molecules, BS-Tat-Ni-NTA, MV1-Tat-Ni-NTA, BS-R9-Ni-NTA, and MV1-R9-Ni-NTA, efficiently degraded His-tagged cellular retinoic acid binding protein 2 via the ubiquitin-proteasome system (UPS). This system will become a useful tool for research into selective protein degradation inducers that act via the UPS.

摘要

我们基于对与目标蛋白（POI）融合的His标签的识别，设计并合成了用于蛋白质敲低方法的杂合分子。合成的目标蛋白降解诱导剂包含三个功能部分：一个His标签配体（次氮基三乙酸镍[Ni-NTA]）、一个E3配体（贝他汀[BS]或MV1）和一个载体肽（Tat或九聚精氨酸[R9]）。设计的杂合分子，即BS-Tat-Ni-NTA、MV1-Tat-Ni-NTA、BS-R9-Ni-NTA和MV1-R9-Ni-NTA，通过泛素-蛋白酶体系统（UPS）有效降解His标签化的细胞视黄酸结合蛋白2。该系统将成为研究通过UPS起作用的选择性蛋白降解诱导剂的有用工具。