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Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy
Understanding how potent neutralizing antibodies (NAbs) inhibit SARS-CoV-2 is critical for effective therapeutic development. We previously described BD-368-2, a SARS-CoV-2 NAb with high potency; however, its neutralization mechanism is largely unknown. Here, we report the 3.5-Å cryo-EM structure of...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489885/ https://www.ncbi.nlm.nih.gov/pubmed/32970990 http://dx.doi.org/10.1016/j.cell.2020.09.035 |
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author | Du, Shuo Cao, Yunlong Zhu, Qinyu Yu, Pin Qi, Feifei Wang, Guopeng Du, Xiaoxia Bao, Linlin Deng, Wei Zhu, Hua Liu, Jiangning Nie, Jianhui Zheng, Yinghui Liang, Haoyu Liu, Ruixue Gong, Shuran Xu, Hua Yisimayi, Ayijiang Lv, Qi Wang, Bo He, Runsheng Han, Yunlin Zhao, Wenjie Bai, Yali Qu, Yajin Gao, Xiang Ji, Chenggong Wang, Qisheng Gao, Ning Huang, Weijin Wang, Youchun Xie, X. Sunney Su, Xiao-dong Xiao, Junyu Qin, Chuan |
author_facet | Du, Shuo Cao, Yunlong Zhu, Qinyu Yu, Pin Qi, Feifei Wang, Guopeng Du, Xiaoxia Bao, Linlin Deng, Wei Zhu, Hua Liu, Jiangning Nie, Jianhui Zheng, Yinghui Liang, Haoyu Liu, Ruixue Gong, Shuran Xu, Hua Yisimayi, Ayijiang Lv, Qi Wang, Bo He, Runsheng Han, Yunlin Zhao, Wenjie Bai, Yali Qu, Yajin Gao, Xiang Ji, Chenggong Wang, Qisheng Gao, Ning Huang, Weijin Wang, Youchun Xie, X. Sunney Su, Xiao-dong Xiao, Junyu Qin, Chuan |
author_sort | Du, Shuo |
collection | PubMed |
description | Understanding how potent neutralizing antibodies (NAbs) inhibit SARS-CoV-2 is critical for effective therapeutic development. We previously described BD-368-2, a SARS-CoV-2 NAb with high potency; however, its neutralization mechanism is largely unknown. Here, we report the 3.5-Å cryo-EM structure of BD-368-2/trimeric-spike complex, revealing that BD-368-2 fully blocks ACE2 recognition by occupying all three receptor-binding domains (RBDs) simultaneously, regardless of their “up” or “down” conformations. Also, BD-368-2 treats infected adult hamsters at low dosages and at various administering windows, in contrast to placebo hamsters that manifested severe interstitial pneumonia. Moreover, BD-368-2’s epitope completely avoids the common binding site of VH3-53/VH3-66 recurrent NAbs, evidenced by tripartite co-crystal structures with RBDs. Pairing BD-368-2 with a potent recurrent NAb neutralizes SARS-CoV-2 pseudovirus at pM level and rescues mutation-induced neutralization escapes. Together, our results rationalized a new RBD epitope that leads to high neutralization potency and demonstrated BD-368-2’s therapeutic potential in treating COVID-19. |
format | Online Article Text |
id | pubmed-7489885 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-74898852020-09-15 Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy Du, Shuo Cao, Yunlong Zhu, Qinyu Yu, Pin Qi, Feifei Wang, Guopeng Du, Xiaoxia Bao, Linlin Deng, Wei Zhu, Hua Liu, Jiangning Nie, Jianhui Zheng, Yinghui Liang, Haoyu Liu, Ruixue Gong, Shuran Xu, Hua Yisimayi, Ayijiang Lv, Qi Wang, Bo He, Runsheng Han, Yunlin Zhao, Wenjie Bai, Yali Qu, Yajin Gao, Xiang Ji, Chenggong Wang, Qisheng Gao, Ning Huang, Weijin Wang, Youchun Xie, X. Sunney Su, Xiao-dong Xiao, Junyu Qin, Chuan Cell Article Understanding how potent neutralizing antibodies (NAbs) inhibit SARS-CoV-2 is critical for effective therapeutic development. We previously described BD-368-2, a SARS-CoV-2 NAb with high potency; however, its neutralization mechanism is largely unknown. Here, we report the 3.5-Å cryo-EM structure of BD-368-2/trimeric-spike complex, revealing that BD-368-2 fully blocks ACE2 recognition by occupying all three receptor-binding domains (RBDs) simultaneously, regardless of their “up” or “down” conformations. Also, BD-368-2 treats infected adult hamsters at low dosages and at various administering windows, in contrast to placebo hamsters that manifested severe interstitial pneumonia. Moreover, BD-368-2’s epitope completely avoids the common binding site of VH3-53/VH3-66 recurrent NAbs, evidenced by tripartite co-crystal structures with RBDs. Pairing BD-368-2 with a potent recurrent NAb neutralizes SARS-CoV-2 pseudovirus at pM level and rescues mutation-induced neutralization escapes. Together, our results rationalized a new RBD epitope that leads to high neutralization potency and demonstrated BD-368-2’s therapeutic potential in treating COVID-19. Elsevier Inc. 2020-11-12 2020-09-14 /pmc/articles/PMC7489885/ /pubmed/32970990 http://dx.doi.org/10.1016/j.cell.2020.09.035 Text en © 2020 Elsevier Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Article Du, Shuo Cao, Yunlong Zhu, Qinyu Yu, Pin Qi, Feifei Wang, Guopeng Du, Xiaoxia Bao, Linlin Deng, Wei Zhu, Hua Liu, Jiangning Nie, Jianhui Zheng, Yinghui Liang, Haoyu Liu, Ruixue Gong, Shuran Xu, Hua Yisimayi, Ayijiang Lv, Qi Wang, Bo He, Runsheng Han, Yunlin Zhao, Wenjie Bai, Yali Qu, Yajin Gao, Xiang Ji, Chenggong Wang, Qisheng Gao, Ning Huang, Weijin Wang, Youchun Xie, X. Sunney Su, Xiao-dong Xiao, Junyu Qin, Chuan Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy |
title | Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy |
title_full | Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy |
title_fullStr | Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy |
title_full_unstemmed | Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy |
title_short | Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy |
title_sort | structurally resolved sars-cov-2 antibody shows high efficacy in severely infected hamsters and provides a potent cocktail pairing strategy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489885/ https://www.ncbi.nlm.nih.gov/pubmed/32970990 http://dx.doi.org/10.1016/j.cell.2020.09.035 |
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