Emerg Microbes Infect . An engineered 5-helix bundle derived from SARS-CoV-2 S2 pre-binds sarbecoviral spike at both serological- and endosomal-pH to inhibit virus entry

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Emerg Microbes Infect


. 2022 Jun 27;1-50.
doi: 10.1080/22221751.2022.2095308. Online ahead of print.
An engineered 5-helix bundle derived from SARS-CoV-2 S2 pre-binds sarbecoviral spike at both serological- and endosomal-pH to inhibit virus entry


Xi Lin ¹ , Liyan Guo ¹ , Sheng Lin ¹ , Zimin Chen ¹ , Fanli Yang ¹ , Jing Yang ¹ , Lingling Wang ¹ , Ao Wen ¹ , Yanping Duan ¹ , Xindan Zhang ¹ , Yushan Dai ¹ , Keqing Yin ¹ , Xin Yuan ¹ , Chongzhang Yu ¹ , Bin He ¹ , Yu Cao ^{1 2} , Haohao Dong ³ , Jian Li ⁴ , Qi Zhao ⁵ , Guangwen Lu ¹



Affiliations

• PMID: 35757908
• DOI: 10.1080/22221751.2022.2095308

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: Broad-spectrum inhibition/5-helix bundle (5HB)/SARS-CoV-2/Structural basis/Viral entry.