一种重新设计的药物干扰核酸,以抑制新冠病毒Nsp13的双重活动
Nathan Soper1, Isabelle Yardumian1, Eric Chen1,2
1Department of Chemistry, New York University, New York, New York 10003, United States.
ACS chemical biology
|July 9, 2024
概括
一种名为IOWH-032的新药有效抑制了SARS-CoV-2 Nsp13螺旋酶的活性. 这一发现提供了一个有前途的新抗病毒策略来对抗SARS-CoV-2及其变种.
科学领域:
- 病毒学 病毒学
- 药物发现 药物发现 药物发现
- 结构生物学 结构生物学
背景情况:
- 随着COVID-19的爆发,人们越来越需要新型抗病毒疗法.
- 严重急性呼吸道综合征冠状病毒2 (SARS-CoV-2) 非结构性蛋白13 (Nsp13) 是病毒复制的关键螺旋酶,也是尚未探索的治疗标.
- 开发病毒酶的小分子抑制剂是具有挑战性的,因为蛋白质的灵活性和识别连接体结合口袋.
研究的目的:
- 通过虚拟查,识别SARS-CoV-2 Nsp13螺旋酶的潜在配体.
- 描述已识别的化合物的抑制机制和选择性.
- 验证针对SARS-CoV-2的已识别的抑制剂的治疗潜力.
主要方法:
- 在药物库中进行虚拟选,以识别Nsp13配体.
- 生物化学试验测量ATPase和Heliase活动.
- 动力和结合测试,计算建模和突变分析.
- 针对微生物螺旋酶的选择性分析和针对SARS-CoV-2变种的测试.
主要成果:
- 一种离子通道抑制剂IOWH-032被确定为在低微分子度下,SARS-CoV-2 Nsp13化酶和ATPase活动的强有力的抑制剂.
- IOWH-032与RNA结合接口结合,取代核酸基质,但不取代ATP.
- 该化合物对其他微生物螺旋酶的冠状病毒Nsp13具有选择性,并保留了来自SARS-CoV-2变种的Nsp13的活性.
- 已经证明IOWH-032可以降低人体细胞中的SARS-CoV-2病毒载荷.
结论:
- IOWH-032是一种新的,选择性的SARS-CoV-2 Nsp13抑制剂,为抗病毒药物开发提供了新的途径.
- 这些发现为IOWH-032的抗病毒活性提供了机制基础,并支持其作为治疗剂的潜力.
- 这项研究为发现额外的强大的调节器,准病毒螺旋酶的发现铺平了道路.
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