Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related sarbecoviruses enter host cells by receptor-recognition and membrane-fusion. An indispensable step in fusion is the formation of 6-helix bundle by viral spike heptad repeats 1 and 2 (HR1 and HR2). Here, we report the construction of 5-helix bundle (5HB) proteins for virus infection inhibition. The optimal construct inhibits SARS-CoV-2 pseudovirus entry with sub-micromolar IC50. Unlike HR2-based peptides that cannot bind spike in the pre-fusion conformation, 5HB features with the capability of binding to pre-fusion spike. Furthermore, 5HB binds viral HR2 at both serological- and endosomal-pH, highlighting its entry-inhibition capacity when SARS-CoV-2 enters via either cell membrane fusion or endosomal route. Finally, we show that 5HB could neutralize S-mediated entry of the predominant SARS-CoV-2 variants and a wide spectrum of sarbecoviruses. These data provide proof-of-concept evidence that 5HB might be developed for the prevention and treatment of SARS-CoV-2 and other emerging sarbecovirus infections.
Keywords: 5-helix bundle (5HB); Broad-spectrum inhibition; SARS-CoV-2; structural basis; viral entry.
【저자키워드】 SARS-CoV-2, viral entry., 5-helix bundle (5HB), Broad-spectrum inhibition, structural basis, 【초록키워드】 Treatment, severe acute respiratory syndrome coronavirus 2, coronavirus, SARS-CoV-2 variant, peptide, severe acute respiratory syndrome Coronavirus, viral entry, IC50, Protein, infections, SARS-CoV-2 variants, peptides, SARS-CoV-2 pseudovirus, virus infection, fusion, serological, Sarbecoviruses, binding, sarbecovirus, Evidence, host cells, can not, host cell, acute respiratory syndrome, acute respiratory syndrome coronavirus, These data, viral spike, construction, cell membrane, heptad repeat, pre-fusion, feature, neutralize, bind, inhibit, predominant, highlighting, sarbecovirus, 【제목키워드】 virus entry, serological, SARS-CoV-2 S2, inhibit,