对于SARS-CoV-2 Mpro E166变体的药物耐药性变化的结构基础
Morgan A Esler1,2, Ke Shi1,2, Joseph A Rollie1,2
1Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.
mBio
|June 2, 2025
概括
一种SARS-CoV-2 Mpro突变 (E166V) 通过改变蛋白酶结构导致耐药性. 这项研究揭示了E166V如何影响抗病毒结合,有助于开发下一代SARS-CoV-2抑制剂.
科学领域:
- 病毒学 病毒学
- 结构生物学 结构生物学
- 药物发现 药物发现 药物发现
背景情况:
- 严重急性呼吸道综合征冠状病毒2 (SARS-CoV-2) 主蛋白酶 (Mpro) 是抗病毒疗法的关键目标.
- 该Mpro E166V突变赋予显著的耐药性临床使用的抑制剂,如尼尔马特里尔维尔,需要机械的理解.
研究的目的:
- 阐明SARS-CoV-2 Mpro E166V介导的耐药性背后的分子机制.
- 调查耐尼马特里尔维尔,恩西特里尔维尔和博富特里尔维尔耐药性的结构基础.
主要方法:
- 用X射线晶体学来确定SARS-CoV-2 Mpro E166V与抑制剂复合的结构.
- 生物化学分析,包括热稳定性测定,以评估抑制剂的结合和抵抗.
主要成果:
- 晶体结构显示,E166V通过失去键和硬质碰撞引起阻力,特别是与nirmatrelvir.
- 博富特里尔维尔表现出更大的结合灵活性,有可能减轻突变活性部位的硬质障碍.
- 热稳定性数据证实了E166V对抑制剂结合的差异性影响,尼尔马特里尔维尔受影响最大.
结论:
- 在SARS-CoV-2 Mpro中的E166V突变通过影响抑制剂结合的结构性改变赋予了耐药性.
- 了解这些耐药机制对于设计下一代抗病毒药物对抗耐药病毒菌株有效至关重要.
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