带有基链的烯是多价值杀毒抗病毒药物的通用支架
Yong Zhu1, Matteo Gasbarri1, Soumaila Zebret1
1Institute of Materials, École Polytechnique Fédérale de Lausanne, Station 12, 1015 Lausanne, Switzerland.
新的广谱抗病毒药物通过模仿细胞表面部分来实现不可逆转的抑制. 这些修改后的多价值进入抑制剂显示对SARS-CoV-2和流感病毒的疗效,即使在稀释后.
科学领域:
- 病毒学 病毒学
- 药物发现 药物发现 药物发现
- 生物化学 生物化学
背景情况:
- 病毒通过结合细胞表面的葡萄糖蛋白,如肝硫酸蛋白质糖 (HSPG) 和酸 (SA) 来启动感染.
- 广谱多价值进入抑制剂 (MEI) 模仿这些部分,但通常表现出可逆抑制,由于度依赖的损失,限制了它们的治疗疗效.
- 现有的模仿HSPG的MEI只显示了对SARS-CoV-2的可逆抑制.
研究的目的:
- 开发具有广谱抗病毒活性不可逆转的抑制机制的新型MEI.
- 确定设计原则,以创建针对SARS-CoV-2和流感等病毒有效的不可逆转的MEI.
- 评估这些新型不可逆转的MEI的体内疗效.
主要方法:
- 对具有核心,疏水臂和模仿HSPG的小分子进行系统的研究.
- 测试各种病毒的抑制可逆性,包括SARS-CoV-2.
- 在叙利亚仓鼠模型中进行的SARS-CoV-2的体内疗效研究,使用鼻内和气溶给药.
- 开发和测试模仿SA的MEI.
主要成果:
- 识别具有针对一系列病毒的不可逆转抑制的MEI,包括SARS-CoV-2.
- 在感染后12小时,通过鼻内和气溶途径在子中对SARS-CoV-2进行不可逆转的MEI治疗疗效的证明.
- 成功地应用了设计规则,以创建模仿SA的MEI,对流感病毒具有不可逆转的抑制作用.
结论:
- 对MEI的疏水臂修改可以实现不可逆转的抑制,克服度依赖的疗效损失.
- 开发的不可逆转的MEI显示出针对SARS-CoV-2和流感病毒的显著治疗潜力.
- 建立的设计原则适用于创建下一代宽频抗病毒进入抑制剂.
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