Heterologous sarbecovirus receptor binding domains as scaffolds for SARS-CoV-2 receptor binding motif presentation.
Heterologous sarbecovirus receptor binding domains as scaffolds for SARS-CoV-2 receptor binding motif presentation.
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异源 sarbecovirus 受体结合域作为 SARS-CoV-2 受体结合基序呈现的支架。
DOI：
10.1101/2023.08.21.554179
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Schmidt,AaronG
中科院分区：
文献类型：
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作者：
Hauser,BlakeM;Sangesland,Maya;Lam,EvanC;Denis,KerriJSt;Sheehan,MaeganL;Vu,MyaL;Cheng,AgnesH;Balazs,AlejandroB;Lingwood,Daniel;Schmidt,AaronG
结构引导的合理免疫原设计可以产生引发期望的体液应答的优化的免疫原。设计策略通常集中在靶向病毒糖蛋白上的保守位点，这些位点最终将赋予有效的中和作用。对于SARS-CoV-2（SARS-2），表面暴露的刺突糖蛋白包括一个广泛保守的部分，受体结合基序（RBM），这是接合宿主细胞受体ACE 2所必需的。扩大对该位点的体液应答可能导致针对多种肉瘤病毒的更有效的中和抗体应答。在这里，我们使用了一种“表面重塑”的方法和迭代设计周期，将SARS-2 RBM移植到异源的肉瘤病毒支架上。选择支架以改变相对于SARS-2的抗原距离，以潜在地集中对RBM的应答。这些免疫原的多聚化版本在先前存在的SARS-2免疫的背景下引起对肉瘤病毒的广泛中和。这些经过验证的工程方法可以帮助为将来的Sarbecoviruses免疫原设计工作提供信息，并且通常适用于其他病毒。
Structure-guided rational immunogen design can generate optimized immunogens that elicit a desired humoral response. Design strategies often center on targeting conserved sites on viral glycoproteins that will ultimately confer potent neutralization. For SARS-CoV-2 (SARS-2), the surface-exposed spike glycoprotein includes a broadly conserved portion, the receptor binding motif (RBM), that is required to engage the host cellular receptor, ACE2. Expanding humoral responses to this site may result in a more potent neutralizing antibody response against diverse sarbecoviruses. Here, we used a “resurfacing” approach and iterative design cycles to graft the SARS-2 RBM onto heterologous sarbecovirus scaffolds. The scaffolds were selected to vary the antigenic distance relative to SARS-2 to potentially focus responses to RBM. Multimerized versions of these immunogens elicited broad neutralization against sarbecoviruses in the context of preexisting SARS-2 immunity. These validated engineering approaches can help inform future immunogen design efforts for sarbecoviruses and are generally applicable to other viruses.