利用BET-基域辅助的核进口用于针对性的亚细胞定位和增强反意义核酸的效率
Disha Kashyap1,2, Martina Cadeddu3, Peter L Oliver3
1Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
Journal of the American Chemical Society
|August 4, 2025
概括
反感性寡核酸 (ASO) 需要核传递来进行基因调制. 将ASO与 (+) -JQ1作为核进口物结合,提高了它们的治疗效果和核定位,从而改善了基因沉默.
科学领域:
- 生物化学
- 分子生物学
- 提供药物
背景情况:
- 反感性寡核酸 (ASO) 是调节基因表达的治疗药物.
- 包括拼接切换和mRNA降解在内的ASO机制主要发生在细胞核中.
- 有效的核输送对于最大化ASO治疗效果至关重要.
研究的目的:
- 开发ASO结合物,以加强积极的核进口.
- 通过与小分子核进口物的共价结合来提高ASO的有效性, (+) -JQ1.
- 展示这一策略在重新评估以前失败的ASO疗法方面的潜力.
主要方法:
- 通过对ASO与 (+) -JQ1进行共价连接来合成ASO合物.
- 在各种细胞系中评估 (+) -JQ1-ASO结合物的结合切换和mRNA倒置活动.
- 使用亚细胞分离和免疫细胞化学评估改性ASO的核定位.
主要成果:
- 与未经修改的ASO相比, (+) -JQ1-ASO结合物显示出更好的拼接切换和mRNA敲击.
- 增强的疗效与改性ASO的核定位增加相关.
- 在急性髓性白血病模型中改善了Oblimersen (BCL- 2 ASO) 的性能.
结论:
- 与核进口商 (+) -JQ1 进行 ASO 的共价修改显著提高了核输送和目标效率.
- 这一战略有望开发更有效的ASO疗法.
- 使用这种增强的输送方法,可能需要对像Oblimersen这样的ASO药物进行重新评估.
相关概念视频
01:46Nuclear Localization Signals and Import
6.0K
Proteins targeted to the nucleus carry short stretches of amino acid sequences called the nuclear localization signal or NLS. Classical nuclear localization signals are of two types: monopartite and bipartite NLS. Monopartite classical NLS (cNLS) consists of a single cluster of 4-8 amino acids. Bipartite cNLS consists of two clusters of 2-3 amino acids and a 9-12 residue long proline-rich linker bridging the two clusters. Signal clusters are rich in positively charged amino acids such as...
6.0K
01:34Nuclear Protein Sorting
4.8K
Nuclear protein sorting is the selective trafficking of histones, polymerases, gene regulatory proteins into the nucleus and exporting RNAs and ribosomes to the cytosol. It is a tightly controlled process that regulates gene expression within a cell.
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...
4.8K
01:45Regulation of Nuclear Protein Sorting
2.4K
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
2.4K
01:42Directionality of Nuclear Transport
3.5K
Ras-related nuclear protein or Ran is a small G protein that cycles between its GTP and GDP bound states. Ran specific regulators, a Ran GTPase Activating Protein or RanGAP present in the cytosol and a Ran guanine nucleotide exchange factor or RanGEF present inside the nucleus regulate GTP/GDP exchange. A high concentration of GTP inside the cells, in addition to this asymmetric distribution of Ran-specific regulators, leads to a higher RanGTP concentration inside the nucleus. This...
3.5K