开发一种双层,稳定α-螺旋和β-叶结构,以降低转录因子AR-V7的降解作用
Bohan Ma1, Donghua Liu1, Mengjun Zheng2
1Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710049, China.
JACS Au
|March 1, 2024
概括
我们开发了一种新的双级类药物DSARTC,可以降解雄激素受体 (AR) 和AR-V7. 这种PROTAC候选显示出增强的稳定性和细胞透性,抑制了抗性前列腺癌的生长.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 类药物在稳定性和细胞透方面面临着挑战.
- 碳化合物接提高了稳定性,但对β片结构效果较差.
研究的目的:
- 设计一种能够稳定α-螺旋和β-叶结构的新型双层.
- 创建一种基于的PROTAC,针对雄激素受体 (AR) 和其变体AR-V7.
主要方法:
- 一个异质-合规双阶 (DSARTC) 的设计.
- 利用分子动力学模拟和循环二元化进行结构验证.
- 在动物模型中测试了DSARTC,用于抗恩扎胺胺的前列腺癌.
主要成果:
- DSARTC成功地稳定了α-螺旋和β-板结构.
- 与线性相比,DSARTC表现出较强的稳定性和细胞透性.
- 在体内,DSARTC抑制了瘤生长,并降低了AR和AR-V7蛋白水平.
结论:
- DSARTC 是一流的异构形态双层类PROTAC.
- 这种方法提供了一个有前途的策略,以准无毒转录因子.
- DSARTC显示出作为AR-V7驱动的前列腺癌的强效治疗药物的潜力.
更多相关视频
相关概念视频
Protein Folding
8.0K
Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
8.0K
Proteins: From Genes to Degradation
12.2K
Within a biological system, the DNA encodes the RNA, and the nucleotide sequence in the RNA further defines the amino acid sequence in the protein. This is referred to as “The Central Dogma of Molecular Biology” - a term coined by Francis Crick. Central dogma is a firm principle in biology that defines the flow of genetic information within any life form. The two fundamental steps in central dogma are - transcription and translation.
Transcription is the synthesis of RNA...
Transcription is the synthesis of RNA...
12.2K
mRNA Stability and Gene Expression
5.6K
The structure and stability of mRNA molecules regulates gene expression, as mRNAs are a key step in the pathway from gene to protein. In eukaryotes, the half-life of mRNA varies from a few minutes up to several days. mRNA stability is essential in growth and development. The absence of the proteins regulating its stability, such as tristetraprolin in mice, can cause systemic issues, including bone marrow overgrowth, inflammation, and autoimmunity.
Cis-acting Elements involved in mRNA stability
Cis-acting Elements involved in mRNA stability
5.6K
RNA Stability
33.5K
Intact DNA strands can be found in fossils, while scientists sometimes struggle to keep RNA intact under laboratory conditions. The structural variations between RNA and DNA underlie the differences in their stability and longevity. Because DNA is double-stranded, it is inherently more stable. The single-stranded structure of RNA is less stable but also more flexible and can form weak internal bonds. Additionally, most RNAs in the cell are relatively short, while DNA can be up to 250 million...
33.5K
Leaky Scanning
5.1K
During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA. Marilyn Kozak discovered that the sequence RCCAUGG (where R...
5.1K
Protein Organization
137.7K
Overview
137.7K


