复旦大学孙晓玉团队近日取得一项新成果。经过不懈努力，他们的最新研究提出了奥密克戎刺突融合中间体中抗体结合的立体位阻。2026年5月6日出版的《自然》杂志发表了这项成果。

通过综合功能和结构分析，该课题组人员证明了76E1（一种靶向刺突残基815-825的抗体）特异性识别一个开放的早期融合中间构象，其中该表位采用螺旋构象，称为S2'-helix。SARS-CoV-2组粒变体通过S2'-螺旋位移和早期融合中间构象中限制S1-ACE2距离造成的位阻，以及对组织蛋白酶介导的进入的依赖增加，从而削弱76E1对S2'切割的抑制，从而逃避这些抗体。H655Y突变是这种逃避的核心。抗体大小直接影响其进入S2'-螺旋。至关重要的是，抗体大小最小化逆转了逃避机制，并显著增强了对真实的Omicron变体和其他人类冠状病毒主题（包括SARS-CoV-1和HCoV-229E）的中和活性。这些发现确定了小分子靶向S2'-螺旋作为泛冠状病毒治疗的策略。

据了解，了解冠状病毒刺突蛋白的构象变化对于开发广谱治疗方法至关重要。泛冠状病毒表位刺突残基815-825（以S2'位点为中心）隐藏在前置刺突中，但在ACE2结合时短暂暴露。

附：英文原文

Title: Steric hindrance of antibody binding in an Omicron spike fusion intermediate

Author: Bao, Zhiheng, Liu, Zhimin, Zhang, Zhaoyong, Wang, Xuanjia, Jin, Xiaohui, Bai, Jiaxiu, Ma, Hanwen, Li, Yaxin, Yi, Chunyan, Ling, Zhiyang, Huang, Zhong, Zhang, Lu, Chen, Zhenguo, Xie, Youhua, Wang, Yanqun, Sun, Lei, Sun, Xiaoyu

Issue&Volume: 2026-05-06

Abstract: Understanding conformational changes of the coronavirus spike protein is critical for developing broad-spectrum therapies. The pan-coronavirus epitope spike residues 815–825 (centred on the S2′ site) are buried in the prefusion spike but are transiently exposed upon ACE2 binding1,2. Here, using integrated functional and structural analyses, we demonstrate that 76E1, an antibody targeting spike residues 815–825, specifically recognizes an open early fusion intermediate conformation in which this epitope adopts a helical conformation, designated the S2′-helix. SARS-CoV-2 Omicron variants evade such antibodies via steric hindrance resulting from S2′-helix shifts and restricted S1–ACE2 distancing in the early fusion intermediate conformation, together with increased reliance on cathepsin-mediated entry that impairs 76E1 inhibition of S2′ cleavage. The H655Y mutation is central to this evasion. Antibody size directly affects its access to the S2′-helix. Crucially, antibody size minimization reversed the evasion mechanisms and significantly enhanced neutralizing activity against authentic Omicron variants and other human coronaviruses, including SARS-CoV-1 and HCoV-229E. These findings establish small-molecule targeting of the S2′-helix as a strategy for pan-coronavirus therapies.

DOI: 10.1038/s41586-026-10462-2

Source: https://www.nature.com/articles/s41586-026-10462-2