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在HKU5冠状病毒中ACE2受体利用的融合演变的分子基础

Young-Jun Park¹, Chen Liu², Jimin Lee³

¹Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.

|February 8, 2025

概括

像HKU5这样的Merbecoviruses可以使用ACE2进入细胞,这与之前的理解不同. 一个突变使HKU5能够使用人类的ACE2,帮助应对新出现的病毒.

科学领域:

病毒学
分子生物学
进化生物学

背景情况:

双基酶4 (DPP4) 是已确定的梅尔贝科病毒受体.
最近的发现表明,一些非洲蝙蝠传播的与MERS相关的冠状病毒利用血管酶转化酶2 (ACE2).
在merbecoviruses中ACE2的使用范围和受体热带性在很大程度上是未被探索的.

研究的目的:

调查MERBECOVIRUS HKU5对ACE2的利用情况
确定HKU5的物种热带的分子基础.
评估HKU5的抗原性,并确定潜在的抑制剂.
评估ACE2在merbecovirus演变和出现中的潜力.

主要方法:

使用各种哺乳动物ACE2蛋白质进行细胞进入测试.
定位基因突变以确定关键的氨基酸残留物.
对受体热带的结合方式和分子决定因素的分析.
对HKU5抑制剂进行抗原性分析和药物查.

主要成果:

HKU5利用Pipistrellus abramus (P.abr) 的ACE2和一些非蝙蝠哺乳动物的ACE2.
与其他使用ACE2的冠状病毒相比,观察到不同的结合方式.
鉴定出HKU5ACE2受体结合的一个氨基酸突变,使人类ACE2可利用.
MERS-CoV 和 HKU5 的抗原性显著不同.
在临床试验中发现了几种HKU5抑制剂.

结论:

梅尔贝科病毒的进化包括在不同类型中独立获得ACE2利用.
HKU5通过单一突变使用各种哺乳动物ACE2,包括人类ACE2的能力突出显示了大流行潜力.
这些发现为开发对抗新出现的美尔贝病毒提供了基础.
机器学习可以帮助预测和准备病毒爆发.

关键词:

在HKU5 其他病例抗体冠状病毒虫病毒溢出影响病毒受体

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