Fusogenicity of SARS-CoV-2 BA.2.86 subvariant and its sensitivity to the prokaryotic recombinant EK1 peptide

Abstract

BA.2.86, a novel SARS-CoV-2 Omicron subvariant, has emerged along with widespread concerns since the number of mutations in its S protein exceeds that of other Omicron subvariants (Fig. 1a ). On August 18, 2023, the World Health Organization formally classified BA.2.86 as a variant under monitoring (VUM) 1 . Notably, numerous studies have reported that BA.2.86 has evaded humoral immunity induced by both inactivated and mRNA SARS-CoV-2 vaccines, as well as COVID-19 convalescent plasma 2 , 3 . However, in comparison to previous dominant SARS-CoV-2 Omicron subvariants, the fusogenicity of BA.2.86 and its sensitivity to coronavirus fusion and replication inhibitors have yet to be systematically evaluated. Fig. 1: Fusogenicity of BA.2.86 S protein and the antiviral efficacy of reEK1. a Distinct S protein mutational profile of the Omicron subvariant BA.2.86. b Representative images of cell-cell fusion mediated by 293 T/WT(D614G)-S, BA.1-S, BA.2-S, BA.2.75-S, BA.2.86-S, XBB.1.5-S, EG.5-S, or negative control after coculture for 8 h. Scale bars, 150 µm. c Rate of fusion mediated by WT(D614G)-S, BA.1-S, BA.2-S, BA.2.75-S, BA.2.86-S, XBB.1.5-S and EG.5-S proteins on Calu-3 cells after coculture for 2, 4, 8 and 24 h. As compared with the BA.2.86 group, asterisks indicate significant differences (* P < 0.05; ** P < 0.01; *** P < 0.001, **** P < 0.0001). d Alteration of fusion capacity mediated by S939F mutation in the HR1 region. e Effect of S939F mutation on the prefusion state of S protein. Surface representation displays the structure of WT S trimer (PDB entry 7WGV) with S939 residue highlighted in yellow. Predicted structure of the S939F mutant was obtained from the SWISS-MODEL server. Zoomed-in view depicts the local region surrounding S939 and F939, as represented in cartoon form. Crucial residues are depicted as sticks and labeled accordingly. f Schematic representation of prokaryotic expression system for production of reEK1 peptide. g Efficacy of reEK1 and EK1 peptides against BA.2.86-S-mediated cell–cell fusion. h Quantitative analysis of the inhibitory activity of reEK1 and EK1 peptides against BA.2.86 PsV infection. i Schematic representation of in vivo protective experiments of reEK1 through aerosolization inhalation route against BA.2 variant challenge in Tgtn (CAG-human ACE2-IRES-Luciferase) mouse model. j Quantitative analysis of viral titer reduction by reEK1 protection against authentic BA.2 variant in Tgtn (CAG-human ACE2-IRES-Luciferase) mouse model. k Protective efficacy of reEK1 against BA.2.86 infection that causes histopathological changes in mouse lung tissues. Scale bars, 100 µm. Full size image

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