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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Inc. 2020
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.
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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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