A bovine antibody possessing an ultralong complementarity-determining region CDRH3 targets a highly conserved epitope in sarbecovirus spike proteins.
A bovine antibody possessing an ultralong complementarity-determining region CDRH3 targets a highly conserved epitope in sarbecovirus spike proteins.
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DOI：
10.1016/j.jbc.2022.102624
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发表时间：
2022-12
影响因子：
4.8
通讯作者：
Boyes, Joan
中科院分区：
文献类型：
--
作者：
Burke, Matthew J.;Scott, James N. F.;Minshull, Thomas C.;Gao, Zeqian;Manfield, Iain;Savic, Sinisa;Stockley, Peter G.;Calabrese, Antonio N.;Boyes, Joan
广泛中和抗体由于其识别在病毒变体中很少突变的高度保守表位的能力而具有作为新型抗病毒治疗剂的巨大潜力。牛抗体的一个子集具有超长的互补决定区（CDR）H3，非常善于识别这些保守的表位，但它们对Sarbecovirus刺突蛋白的反应性尚未被探索过。在这里，我们使用一个SARS-naïve库，以分离广泛的反应性牛CDRH 3结合的受体结合域的SARS-CoV，SARS-CoV-2，和所有SARS-CoV-2的变种。我们进一步表明，它中和病毒假型与SARS冠状病毒刺突，但这不是通过竞争与血管紧张素转换酶2（ACE 2）的结合。相反，使用差分氢-氘交换质谱，我们证明，它认识到的主要网站的脆弱性Sarbecoviruses。该聚糖屏蔽的隐蔽表位仅通过刺突蛋白的结构域间移动而瞬时可用，使得抗体结合触发融合前复合物的破坏。这项原理证明研究证明了体外表达的具有超长CDRH 3的牛抗体用于分离新型、广泛反应性工具以对抗新出现的病原体和鉴定疫苗开发的关键表位的能力。
Broadly neutralizing antibodies have huge potential as novel antiviral therapeutics due to their ability to recognize highly conserved epitopes that are seldom mutated in viral variants. A subset of bovine antibodies possess an ultralong complementarity-determining region (CDR)H3 that is highly adept at recognizing such conserved epitopes, but their reactivity against Sarbecovirus Spike proteins has not been explored previously. Here, we use a SARS-naïve library to isolate a broadly reactive bovine CDRH3 that binds the receptor-binding domain of SARS-CoV, SARS-CoV-2, and all SARS-CoV-2 variants. We show further that it neutralizes viruses pseudo-typed with SARS-CoV Spike, but this is not by competition with angiotensin-converting enzyme 2 (ACE2) binding. Instead, using differential hydrogen-deuterium exchange mass spectrometry, we demonstrate that it recognizes the major site of vulnerability of Sarbecoviruses. This glycan-shielded cryptic epitope becomes available only transiently via interdomain movements of the Spike protein such that antibody binding triggers destruction of the prefusion complex. This proof of principle study demonstrates the power of in vitro expressed bovine antibodies with ultralong CDRH3s for the isolation of novel, broadly reactive tools to combat emerging pathogens and to identify key epitopes for vaccine development.
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DOI：
10.1016/j.jbc.2022.101772
发表时间：
2022-04
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影响因子：
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