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Development of a Small Hybrid Molecule That Mediates Degradation of His-Tag Fused Proteins
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2017-05-01 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00413 Koyo Okitsu 1, 2 , Takayuki Hattori 3 , Takashi Misawa 1 , Takuji Shoda 1 , Masaaki Kurihara 1 , Mikihiko Naito 3 , Yosuke Demizu 1
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2017-05-01 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00413 Koyo Okitsu 1, 2 , Takayuki Hattori 3 , Takashi Misawa 1 , Takuji Shoda 1 , Masaaki Kurihara 1 , Mikihiko Naito 3 , Yosuke Demizu 1
Affiliation
In recent years, the induction of target–protein degradation via the ubiquitin–proteasome system (UPS) mediated by small molecules has attracted attention, and this approach has applications in pharmaceutical development. However, this technique requires a ligand for the target protein that can be incorporated into tailor-made molecules, and there are many proteins for which such ligands have not been found. In this study, we developed a protein-knockdown method that recognizes a His-tag fused to a protein of interest. This strategy theoretically allows comprehensive targeting of proteins of interest by a particular molecule recognizing the tag. As expected, our hybrid molecule 10 [SNIPER(CH6)] efficiently degraded His-tagged CRABP-II and Smad2 in cells. This system provides an easy method to determine the susceptibility of proteins of interest to UPS-mediated degradation. Furthermore, we hope that this method will become an efficient tool to analyze the function of the UPS.
中文翻译:
介导His-tag融合蛋白降解的小杂种分子的开发
近年来,通过小分子介导的泛素-蛋白酶体系统(UPS)诱导靶标蛋白降解引起了人们的关注,该方法已在药物开发中得到应用。但是,该技术需要可以结合到特制分子中的目标蛋白质的配体,并且许多蛋白质都没有找到这种配体。在这项研究中,我们开发了一种蛋白质击倒方法,该方法可识别与目标蛋白质融合的His标签。从理论上讲,该策略可通过识别标签的特定分子对目标蛋白进行全面靶向。不出所料,我们的杂合分子10[SNIPER(CH6)]有效降解细胞中带有His标签的CRABP-II和Smad2。该系统提供了一种简便的方法来确定目标蛋白质对UPS介导的降解的敏感性。此外,我们希望这种方法将成为分析UPS功能的有效工具。
更新日期:2017-06-28
中文翻译:
介导His-tag融合蛋白降解的小杂种分子的开发
近年来,通过小分子介导的泛素-蛋白酶体系统(UPS)诱导靶标蛋白降解引起了人们的关注,该方法已在药物开发中得到应用。但是,该技术需要可以结合到特制分子中的目标蛋白质的配体,并且许多蛋白质都没有找到这种配体。在这项研究中,我们开发了一种蛋白质击倒方法,该方法可识别与目标蛋白质融合的His标签。从理论上讲,该策略可通过识别标签的特定分子对目标蛋白进行全面靶向。不出所料,我们的杂合分子10[SNIPER(CH6)]有效降解细胞中带有His标签的CRABP-II和Smad2。该系统提供了一种简便的方法来确定目标蛋白质对UPS介导的降解的敏感性。此外,我们希望这种方法将成为分析UPS功能的有效工具。