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定义针对 COVID-19 变体的抗体的中和作用和变构作用。

Defining neutralization and allostery by antibodies against COVID-19 variants.

机构信息

Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore.

Department of Biochemistry, National University of Singapore, Singapore, 117546, Singapore.

出版信息

Nat Commun. 2023 Nov 1;14(1):6967. doi: 10.1038/s41467-023-42408-x.

DOI:10.1038/s41467-023-42408-x
PMID:37907459
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10618280/
Abstract

The changing landscape of SARS-CoV-2 Spike protein is linked to the emergence of variants, immune-escape and reduced efficacy of the existing repertoire of anti-viral antibodies. The functional activity of neutralizing antibodies is linked to their quaternary changes occurring as a result of antibody-Spike trimer interactions. Here, we reveal the conformational dynamics and allosteric perturbations linked to binding of novel human antibodies and the viral Spike protein. We identified epitope hotspots, and associated changes in Spike dynamics that distinguish weak, moderate and strong neutralizing antibodies. We show the impact of mutations in Wuhan-Hu-1, Delta, and Omicron variants on differences in the antibody-induced conformational changes in Spike and illustrate how these render certain antibodies ineffective. Antibodies with similar binding affinities may induce destabilizing or stabilizing allosteric effects on Spike, with implications for neutralization efficacy. Our results provide mechanistic insights into the functional modes and synergistic behavior of human antibodies against COVID-19 and may assist in designing effective antiviral strategies.

摘要

SARS-CoV-2 刺突蛋白不断变化的结构与变异体的出现、免疫逃逸以及现有抗病毒抗体的疗效降低有关。中和抗体的功能活性与其作为抗体-刺突三聚体相互作用的结果而发生的四级变化有关。在这里，我们揭示了与新型人类抗体和病毒刺突蛋白结合相关的构象动力学和变构扰动。我们确定了表位热点以及与区分弱、中和和强中和抗体相关的刺突动力学变化。我们展示了武汉-Hu-1、Delta 和奥密克戎变异体中突变对 Spike 诱导的抗体构象变化的影响，并说明了这些突变如何使某些抗体失效。具有相似结合亲和力的抗体可能会对 Spike 产生稳定或不稳定的变构效应，从而影响中和效果。我们的研究结果为针对 COVID-19 的人类抗体的功能模式和协同行为提供了机制见解，并可能有助于设计有效的抗病毒策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/5e991374a83b/41467_2023_42408_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/b33d572d50aa/41467_2023_42408_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/0751cc924cf6/41467_2023_42408_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/0c5996133f84/41467_2023_42408_Fig6_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/44ad1597d05e/41467_2023_42408_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/77f248a078f6/41467_2023_42408_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/5e991374a83b/41467_2023_42408_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/b33d572d50aa/41467_2023_42408_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/6649507743d7/41467_2023_42408_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/fb0c43650eb5/41467_2023_42408_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/8ca102c3c9ae/41467_2023_42408_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/0751cc924cf6/41467_2023_42408_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/0c5996133f84/41467_2023_42408_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/997fed967cf5/41467_2023_42408_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/44ad1597d05e/41467_2023_42408_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/77f248a078f6/41467_2023_42408_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26b2/10618280/5e991374a83b/41467_2023_42408_Fig10_HTML.jpg

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