通过小分子抑制剂对无药性肺腺癌进行蛋白酶独立蛋白质除
Wei Zhou1,2, Guogui Sun3, Zhen Zhang1
1Beijing National Research Center for Molecular Sciences, Institute of Chemistry, Key Laboratory of Molecular Nanostructure and Nanotechnology , Chinese Academy of Science , Beijing 100190 , China.
Journal of the American Chemical Society
|October 29, 2019
概括
研究人员确定了含有丰富白氨酸的重复蛋白 (LRPPRC) 是致命肺腺癌的驱动因素. 他们开发了一种使用gossypolacetic acid降解LRPPRC的新方法,在模型中显示出显著的抗瘤作用.
科学领域:
- 癌症学
- 分子生物学
- 药物发现
背景情况:
- 肺腺癌 (LUAD) 治疗面临挑战,特别是缺乏可药物突变的侵袭性近位增殖亚型.
- 在致命的LUAD亚型中被确定为一种新型瘤驱动剂.
- 目前的治疗策略与LRPPRC等向蛋白质作斗争,这些蛋白质定位在线粒体中,并独立于蛋白质组降解.
研究的目的:
- 确定新型肺腺癌的治疗点.
- 开发一种超出蛋白质分解的针对性蛋白质破坏的新策略.
- 通过线粒体蛋白酶诱导LRPPRC降解的小分子的选.
主要方法:
- 用细胞SELEX生成的合体来确定LRPPRC作为特定的标.
- 开发了一种APTAMER辅助的高通量选方法,以寻找与LRPPRC结合的小分子.
- 戈西波酸 (GAA) 被确定为一种破坏LRPPRC- 沙佩龙相互作用的化合物,导致线粒体降解.
主要成果:
- 在最恶性的LUAD亚型中,LRPPRC被证实为一种特定且过度表达的蛋白质.
- 戈西波酸 (GAA) 通过促进线粒体蛋白酶的降解有效诱导了LRPPRC.
- 在LRPPRC阳性的患者衍生瘤异种移植模型中,GAA表现出显著的抗瘤作用.
结论:
- 针对性LRPPRC倒置是一种前所未有的肺腺癌的有前途的治疗策略.
- 基于aptamer的查提供了一种可行的方法来识别抗药性癌症标的抑制剂.
- 这项研究提出了一种新的蛋白质淘汰策略,绕过了依赖蛋白酶体的降解途径.
更多相关视频
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
18.5K
11:57Studying Protein Function and the Role of Altered Protein Expression by Antibody Interference and Three-dimensional Reconstructions
Published on: April 21, 2016
7.0K
相关概念视频
02:15Experimental RNAi
7.2K
RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...
7.2K
02:30siRNA - Small Interfering RNAs
18.3K
Small interfering RNAs, or siRNAs, are short regulatory RNA molecules that can silence genes post-transcriptionally, as well as the transcriptional level in some cases. siRNAs are important for protecting cells against viral infections and silencing transposable genetic elements.
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the...
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the...
18.3K