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一种源自 SARS-CoV-2 S2 的工程化 5 螺旋束在血清和内体 pH 下均与沙贝科病毒刺突预结合，从而抑制病毒进入。

An engineered 5-helix bundle derived from SARS-CoV-2 S2 pre-binds sarbecoviral spike at both serological- and endosomal-pH to inhibit virus entry.

机构信息

West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.

Disaster Medicine Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China.

出版信息

Emerg Microbes Infect. 2022 Dec;11(1):1920-1935. doi: 10.1080/22221751.2022.2095308.

DOI:10.1080/22221751.2022.2095308
PMID:35757908
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9359175/
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related sarbecoviruses enter host cells by receptor-recognition and membrane-fusion. An indispensable step in fusion is the formation of 6-helix bundle by viral spike heptad repeats 1 and 2 (HR1 and HR2). Here, we report the construction of 5-helix bundle (5HB) proteins for virus infection inhibition. The optimal construct inhibits SARS-CoV-2 pseudovirus entry with sub-micromolar IC50. Unlike HR2-based peptides that cannot bind spike in the pre-fusion conformation, 5HB features with the capability of binding to pre-fusion spike. Furthermore, 5HB binds viral HR2 at both serological- and endosomal-pH, highlighting its entry-inhibition capacity when SARS-CoV-2 enters via either cell membrane fusion or endosomal route. Finally, we show that 5HB could neutralize S-mediated entry of the predominant SARS-CoV-2 variants and a wide spectrum of sarbecoviruses. These data provide proof-of-concept evidence that 5HB might be developed for the prevention and treatment of SARS-CoV-2 and other emerging sarbecovirus infections.

摘要

严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）和相关的沙贝科病毒通过受体识别和膜融合进入宿主细胞。融合过程中不可缺少的一步是病毒刺突七肽重复 1 和 2（HR1 和 HR2）形成 6 螺旋束。在这里，我们报告了用于病毒感染抑制的 5 螺旋束（5HB）蛋白的构建。最佳构建体以亚微摩尔 IC50 抑制 SARS-CoV-2 假病毒进入。与不能结合预融合构象中刺突的基于 HR2 的肽不同，5HB 具有结合预融合刺突的能力。此外，5HB 在血清和内体 pH 下均可结合病毒 HR2，突出了其在 SARS-CoV-2 通过细胞膜融合或内体途径进入时的进入抑制能力。最后，我们表明 5HB 可以中和 S 介导的主要 SARS-CoV-2 变体和广泛的沙贝科病毒的进入。这些数据提供了概念验证证据，表明 5HB 可能被开发用于预防和治疗 SARS-CoV-2 和其他新兴沙贝科病毒感染。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1236/9359175/193deb1b09fe/TEMI_A_2095308_F0006_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1236/9359175/713b4c0ee0b3/TEMI_A_2095308_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1236/9359175/8b4ffca130b7/TEMI_A_2095308_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1236/9359175/76ac641c59f9/TEMI_A_2095308_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1236/9359175/b296ee686ba9/TEMI_A_2095308_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1236/9359175/40be7a4fa94b/TEMI_A_2095308_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1236/9359175/193deb1b09fe/TEMI_A_2095308_F0006_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1236/9359175/713b4c0ee0b3/TEMI_A_2095308_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1236/9359175/8b4ffca130b7/TEMI_A_2095308_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1236/9359175/76ac641c59f9/TEMI_A_2095308_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1236/9359175/b296ee686ba9/TEMI_A_2095308_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1236/9359175/40be7a4fa94b/TEMI_A_2095308_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1236/9359175/193deb1b09fe/TEMI_A_2095308_F0006_OC.jpg

相似文献

[1]
An engineered 5-helix bundle derived from SARS-CoV-2 S2 pre-binds sarbecoviral spike at both serological- and endosomal-pH to inhibit virus entry.

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[4]
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[5]
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[6]
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[2]
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[3]
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[4]
HR121 targeting HR2 domain in S2 subunit of spike protein can serve as a broad-spectrum SARS-CoV-2 inhibitor intranasal administration.

Acta Pharm Sin B. 2023-5-26

[5]
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Signal Transduct Target Ther. 2023-5-10

[6]
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[7]
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Antiviral Res. 2022-12

[8]
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本文引用的文献

[1]
A Five-Helix-Based SARS-CoV-2 Fusion Inhibitor Targeting Heptad Repeat 2 Domain against SARS-CoV-2 and Its Variants of Concern.

Viruses. 2022-3-13

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Cell. 2022-2-3

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Nature. 2022-2

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Nature. 2022-2

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Science. 2021-9-3

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