作为SARS-CoV-2抑制剂的核酸的合理设计问题
Tatyana A Grigoreva1, Svetlana V Vorona1, Daria S Novikova1
1Laboratory of Molecular Pharmacology, St. Petersburg State Institute of Technology (Technical University), Moskovskii pr., 26, St. Petersburg 190013, Russia.
ACS omega
|August 5, 2024
概括
设计针对保存的SARS-CoV-2RNA区域的新型酸核酸为蛋白质抑制剂提供了一个有希望的替代品. 脊柱结构的修改显著增强了对病毒RNA的结合亲和力.
科学领域:
- 病毒学 病毒学
- 分子生物学分子生物学
- 药用化学 医学化学
背景情况:
- 高度可变的SARS-CoV-2 (严重急性呼吸系统综合征冠状病毒2) 需要除了蛋白质抑制剂之外的替代治疗策略.
- 病毒蛋白抑制剂对像SARS-CoV-2这样快速变异的病毒具有有限的有效性.
- 针对病毒基因组的保存区域,为开发广泛的抗病毒药物提供了一种可行的方法.
研究的目的:
- 调查针对冠状病毒阳性单链RNA ((+) RNA) 的高度保护区域的新型药物的设计.
- 探索非天然核酸 (PNA) 作为治疗SARS-CoV-2的治疗剂的潜力.
- 通过骨干修饰来增强PNAs与向病毒RNA的结合亲和力.
主要方法:
- 利用半刚性对接方法来设计非自然的核酸.
- 研究了修改后的PNAs与冠状病毒 (+) RNA.RNA的保存区域之间的相互作用.
- 合成和表征了具有不同骨干结构的PNAs,包括含有N-(2-氨基乙基) 甘氨酸和piperidine的骨干.
主要成果:
- 证明半刚性对接适用于设计PNAs,不同于基于基础互补性的传统反意义RNA设计.
- 确定过渡到更具形态刚性的含有piperidine的骨干显著增加了PNA与目标RNA的亲和力.
- 通过脊柱结构修改,实现了结合亲和度的大幅增强.
结论:
- 具有修改后的骨干的非自然核酸代表了准保存的病毒RNA序列的有希望的策略.
- 开发的PNA设计方法为像SARS-CoV-2这样的高度变化的病毒提供了对不太有效的蛋白质抑制剂的潜在替代方案.
- 进一步开发形态刚性PNAs可能会导致具有更高效率的新型抗病毒疗法.
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