新的2'-O-基N3'→P5' (Thio) -胺酸作为强有力的反意义剂:物理化学特性和生物活性
Saúl Martínez-Montero1, Vivek K Rajwanshi1, Rajendra K Pandey1
1Janssen Pharmaceutical Companies of Johnson and Johnson, South San Francisco, California, USA.
Nucleic acid therapeutics
|August 28, 2023
概括
具有2'-O-基修饰的新型寡核酸类类似物显示出增强的稳定性和强大的抗病毒活性对抗乙型肝炎病毒. 这些2'-O--NPS化合物是有前途的反意义寡核酸候选人,需要进一步开发.
科学领域:
- 药用化学 医学化学
- 氧核酸治疗药物 治疗药物
- 抗病毒药物发现发现
背景情况:
- 乙型肝炎病毒 (HBV) 感染仍然是一个重大的全球健康挑战,需要新的治疗策略.
- 基于寡核酸的疗法为抗病毒治疗提供了一个有希望的途径,但需要优化稳定性和有效性.
- 改进了物理化学和生物特性的改进过的寡核酸的开发对于推进反意义技术至关重要.
研究的目的:
- 设计,合成和描述新型的2"-O-基核糖核酸酸盐 (2'-O-基-NPO) 和酸酸 (2'-O-基-NPS) 寡核酸类似物.
- 在体外和体内评估这些改性寡核酸对乙型肝炎病毒 (HBV) 的抗病毒活性.
- 评估合成的寡核酸类型的物理化学特性,包括双重稳定性,水解稳定性和脂性.
主要方法:
- 合成包含各种2"-O-基修饰物 (如2'-O-甲基, -O-乙基, -O-基, -O-甲氧乙基) 和3"-氨基糖-酸盐骨干的寡核酸.
- 确定双重化温度 (Tm),以评估对互补的DNA和RNA链的结合亲和力.
- 在pH值5.5的水解稳定性和改性寡核酸的相对脂性评价.
- 在体外和体内评估使用HBV作为模型系统的反感性寡核酸 (ASO) 活性,包括 GalNAc结合的gapmers的皮下输送.
主要成果:
- 合成的2'-O-基-NPO和2'-O-基-NPS寡核酸与互补的核酸形成了稳定的重复体,与未经修改的DNA相比,其化温度更高.
- 与它们的3"-O-对应物相比,这些类似物显示出增强的水解稳定性和增加的脂性.
- GalNAc 结合的 2'-O-MOE-NPS gapmers 通过皮下注射,在体内显示出对HBV的显著抗病毒活性,其表现优于其3"-O-修饰的类似物.
- 观察到的特性表明,主要是C3无-结合-糖果糖形状.
结论:
- 2'-O-alkyl-NPS寡核酸具有有利的物理化学特性,包括增强的稳定性和脂性,使它们适合反感性寡核酸的开发.
- 这些改性寡核酸体对HBV具有强大的抗病毒活性,突出显示了它们的治疗潜力.
- 这些发现支持进一步评估和开发2'-O-alkyl-NPS结构作为新型抗感应疗法,用于乙型肝炎病毒感染.
相关概念视频
01:01Phosphodiester Linkages
100.5K
Overview
Phosphodiester bond forms when a phosphoric acid molecule (H3PO4) links with two hydroxyl groups (–OH) of two other molecules, forming two ester bonds. Two water molecules are released in this process. The phosphodiester bond is commonly found in nucleic acids (DNA and RNA) and plays a critical role in their structure and function.
Phosphodiester Bonds Link Nucleotides Together
DNA and RNA are polynucleotides or long chains of nucleotides that are linked together. A nucleotide is...
Phosphodiester bond forms when a phosphoric acid molecule (H3PO4) links with two hydroxyl groups (–OH) of two other molecules, forming two ester bonds. Two water molecules are released in this process. The phosphodiester bond is commonly found in nucleic acids (DNA and RNA) and plays a critical role in their structure and function.
Phosphodiester Bonds Link Nucleotides Together
DNA and RNA are polynucleotides or long chains of nucleotides that are linked together. A nucleotide is...
100.5K
02:30siRNA - Small Interfering RNAs
16.8K
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...
16.8K
01:29Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
606
Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
606
01:18Indirect-Acting Cholinergic Agonists: Mechanism of Action
1.9K
Indirect-acting cholinergic agonists work by interacting with an enzyme called acetylcholinesterase (AChE) in the synaptic cleft. They can be reversible or irreversible inhibitors and have different effects on the enzyme.
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex,...
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex,...
1.9K