Journal
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
Volume 222, Issue -, Pages 2467-2478Publisher
ELSEVIER
DOI: 10.1016/j.ijbiomac.2022.10.031
Keywords
COVID-19; Fusion inhibitor; Vaccine
Funding
- Consejeria de Economia y Conocimiento, [681032]
- Spanish State Research Agency [ANR-11-LABX-0070_TRANSPLANTEX]
- ERDF/ESF
- ANRS (Agence Nationale de Recherches sur le SIDA et les he patites virales)
- Agence Nationale de la Recherche (ANR) [3.2 TRIDIAG]
- Horizon 2020
- Agence Nationale de la Recherche (ANR)
- INSERM
- Institut Universitaire de France (IUF)
- University of Strasbourg (IDEX UNISTRA)
- Junta de Andalucia (Spain)
- European Regional Development Fund (European Union) INTERREG V program
- EHVA
- Spanish Radiation Synchrotron Source (ALBA) , Barcelona, Spain
- European Synchrotron Radiation Facility (ESRF) , Grenoble, France
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The SARS-CoV-2 spike protein plays a crucial role in virus attachment and fusion with cells. The HR1 and HR2 regions of the spike protein are potential therapeutic targets for COVID-19. A study designed chimeric proteins that mimic stable HR1 helical trimers and strongly bind to HR2, showing broad inhibitory activity against different virus strains. Antibody responses against the HR1 mimetic proteins were found in sera from COVID-19 convalescent donors, but not in sera from uninfected donors.
SARS-CoV-2 spike (S) protein mediates virus attachment to the cells and fusion between viral and cell membranes. Membrane fusion is driven by mutual interaction between the highly conserved heptad-repeat regions 1 and 2 (HR1 and HR2) of the S2 subunit of the spike. For this reason, these S2 regions are interesting therapeutic targets for COVID-19. Although HR1 and HR2 have been described as transiently exposed during the fusion process, no significant antibody responses against these S2 regions have been reported. Here we designed chimeric proteins that imitate highly stable HR1 helical trimers and strongly bind to HR2. The proteins have broad inhibitory activity against WT B.1 and BA.1 viruses. Sera from COVID-19 convalescent donors showed significant levels of reactive antibodies (IgG and IgA) against the HR1 mimetic proteins, whereas these antibody responses were absent in sera from uninfected donors. Moreover, both inhibitory activity and antigenicity of the proteins correlate positively with their structural stability but not with the number of amino acid changes in their HR1 sequences, indicating a conformational and conserved nature of the involved epitopes. Our results reveal previously undetected spike epitopes that may guide the design of new robust COVID-19 vaccines and therapies.
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