tetano
Editor, Senior Moderator
Nature
. 2026 May 6.
doi: 10.1038/s41586-026-10462-2. Online ahead of print.
Steric hindrance of antibody binding in an Omicron spike fusion intermediate
Zhiheng Bao[SUP] #[/SUP][SUP] 1 [/SUP], Zhimin Liu[SUP] #[/SUP][SUP] 1 [/SUP], Zhaoyong Zhang[SUP] #[/SUP][SUP] 2 [/SUP], Xuanjia Wang[SUP] 1 [/SUP], Xiaohui Jin[SUP] 1 [/SUP], Jiaxiu Bai[SUP] 1 [/SUP], Hanwen Ma[SUP] 1 [/SUP], Yaxin Li[SUP] 1 [/SUP], Chunyan Yi[SUP] 3 [/SUP], Zhiyang Ling[SUP] 3 [/SUP], Zhong Huang[SUP] 1 [/SUP], Lu Zhang[SUP] 4 [/SUP], Zhenguo Chen[SUP] 1 [/SUP], Youhua Xie[SUP] 5 6 [/SUP], Yanqun Wang[SUP] 7 [/SUP], Lei Sun[SUP] 8 [/SUP], Xiaoyu Sun[SUP] 9 [/SUP]
Affiliations
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 binding[SUP]1,2[/SUP]. 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.
. 2026 May 6.
doi: 10.1038/s41586-026-10462-2. Online ahead of print.
Steric hindrance of antibody binding in an Omicron spike fusion intermediate
Zhiheng Bao[SUP] #[/SUP][SUP] 1 [/SUP], Zhimin Liu[SUP] #[/SUP][SUP] 1 [/SUP], Zhaoyong Zhang[SUP] #[/SUP][SUP] 2 [/SUP], Xuanjia Wang[SUP] 1 [/SUP], Xiaohui Jin[SUP] 1 [/SUP], Jiaxiu Bai[SUP] 1 [/SUP], Hanwen Ma[SUP] 1 [/SUP], Yaxin Li[SUP] 1 [/SUP], Chunyan Yi[SUP] 3 [/SUP], Zhiyang Ling[SUP] 3 [/SUP], Zhong Huang[SUP] 1 [/SUP], Lu Zhang[SUP] 4 [/SUP], Zhenguo Chen[SUP] 1 [/SUP], Youhua Xie[SUP] 5 6 [/SUP], Yanqun Wang[SUP] 7 [/SUP], Lei Sun[SUP] 8 [/SUP], Xiaoyu Sun[SUP] 9 [/SUP]
Affiliations
- PMID: 42092153
- DOI: 10.1038/s41586-026-10462-2
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 binding[SUP]1,2[/SUP]. 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.