作为强大的抗艾滋病毒化合物的2',3'-二氧化碳-2',3'-二氧化二胺的前核酸
Xiao Jia1, Dominique Schols2, Chris Meier1
1Organic Chemistry, Department of Chemistry, Faculty of Mathematics, Informatics and Natural Sciences, Universität Hamburg, Martin-Luther-King-Platz 6, Hamburg D-20146, Germany.
Journal of medicinal chemistry
|August 30, 2023
概括
研究人员开发了新的核酸前药物,用于增强抗病毒化合物的输送. 这些前药对感染细胞中的HIV-1/2复制具有显著的活性,提供了一个有前途的治疗策略.
科学领域:
- 药用化学 医学化学
- 病毒学 病毒学
- 核酸化学 核酸化学
背景情况:
- 开发有效的前期药物对于改善抗病毒核酸类 analog 的输送和疗效至关重要.
- 现有的疗法面临生物可用性和细胞吸收方面的挑战.
研究的目的:
- 合成和评估三种新型核酸原药系统,以提高d4TDP和d4TMP的输送.
- 评估这些前药物对抗HIV-1/2复制的活性.
主要方法:
- 合成核三酸盐和二酸盐类似物,具有不同的脂性修饰.
- 在CEM细胞提取物和PBS的体外输送研究.
- 使用HIV-逆转录酶 (HIV-RT) 和原始延伸试验的酶分析.
- 在HIV感染细胞中进行抗病毒活性测试.
主要成果:
- 证明了d4TDP和d4TMP的成功输送.
- γ-二基化d4TTP衍生物和d4TDP被HIV-RT接受为基质.
- 几种化合物表现出强烈的抗HIV-1/2活性.
- 与d4T相比,化合物18a的抗HIV活性增加了超过45,000倍,选择性指数为37,000.
结论:
- 开发的核酸原药系统有效地提供抗病毒核酸类似物.
- 这些前药物是HIV-RT的基质,并且在体外表现出显著的抗HIV活性.
- 化合物18a是对抗艾滋病毒感染的进一步开发的非常有力的候选物.
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