Discovery of Nanosota-EB1 and -EB2 as Novel Nanobody Inhibitors Against Ebola Virus Infection.

IF 5.5 1区医学 Q1 MICROBIOLOGY

PLoS Pathogens Pub Date : 2024-12-23 eCollection Date: 2024-12-01 DOI:10.1371/journal.ppat.1012817

Fan Bu, Gang Ye, Kimberly Morsheimer, Alise Mendoza, Hailey Turner-Hubbard, Morgan Herbst, Benjamin Spiller, Brian E Wadzinski, Brett Eaton, Manu Anantpadma, Ge Yang, Bin Liu, Robert Davey, Fang Li

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引用次数: 0

Abstract

The Ebola filovirus (EBOV) poses a serious threat to global health and national security. Nanobodies, a type of single-domain antibody, have demonstrated promising therapeutic potential. We identified two anti-EBOV nanobodies, Nanosota-EB1 and Nanosota-EB2, which specifically target the EBOV glycoprotein (GP). Cryo-EM and biochemical data revealed that Nanosota-EB1 binds to the glycan cap of GP1, preventing its protease cleavage, while Nanosota-EB2 binds to critical membrane-fusion elements in GP2, stabilizing it in the pre-fusion state. Nanosota-EB2 is a potent neutralizer of EBOV infection in vitro and offers excellent protection in a mouse model of EBOV challenge, while Nanosota-EB1 provides moderate neutralization and protection. Nanosota-EB1 and Nanosota-EB2 are the first nanobodies shown to inhibit authentic EBOV. Combined with our newly developed structure-guided in vitro evolution approach, they lay the foundation for nanobody-based therapies against EBOV and other viruses within the ebolavirus genus.

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抗埃博拉病毒感染的新型纳米体抑制剂Nanosota-EB1和-EB2的发现

埃博拉丝状病毒（EBOV）对全球卫生和国家安全构成严重威胁。纳米抗体是一种单域抗体，具有良好的治疗潜力。我们发现了两种特异性靶向EBOV糖蛋白（GP）的抗EBOV纳米体Nanosota-EB1和Nanosota-EB2。Cryo-EM和生化数据显示，Nanosota-EB1与GP1的聚糖帽结合，阻止其蛋白酶裂解，而Nanosota-EB2与GP2的关键膜融合元件结合，使其稳定在融合前状态。Nanosota-EB2是一种有效的体外EBOV感染中和剂，并在EBOV攻击小鼠模型中提供出色的保护，而Nanosota-EB1提供适度的中和和保护。Nanosota-EB1和Nanosota-EB2是第一个被证明能抑制真正EBOV的纳米体。结合我们新开发的结构引导体外进化方法，它们为基于纳米体的治疗埃博拉病毒和埃博拉病毒属的其他病毒奠定了基础。

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来源期刊

PLoS Pathogens MICROBIOLOGY-PARASITOLOGY

自引率

3.00%

发文量

598

期刊介绍： Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.