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. Issue 1 (31st December 2022)

• Record Type: Journal Article
• Authors: Lin, Xi; Guo, Liyan; Lin, Sheng; Chen, Zimin; Yang, Fanli; Yang, Jing; Wang, Lingling; Wen, Ao; Duan, Yanping; Zhang, Xindan; Dai, Yushan; Yin, Keqing; Yuan, Xin; Yu, Chongzhang; He, Bin; Cao, Yu; Dong, Haohao; Li, Jian; Zhao, Qi; Lu, Guangwen
• Is Part Of: Emerging microbes & infections. Volume 11:Issue 1(2022)
• Page Start: 1920
• Page End: 1935
• Publication Date: 2022-12-31
• Subjects: Broad-spectrum inhibition -- 5-helix bundle (5HB) -- SARS-CoV-2 -- structural basis -- viral entry; Medical microbiology -- Periodicals; Communicable diseases -- Periodicals; Infection -- Periodicals; 616.9041
• DOI: 10.1080/22221751.2022.2095308
• Languages: English
• ISSNs: 2222-1751

Abstract

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.