tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Liyan Guo[SUP] 1 [/SUP], Sheng Lin[SUP] 1 [/SUP], Zimin Chen[SUP] 1 [/SUP], Fanli Yang[SUP] 1 [/SUP], Jing Yang[SUP] 1 [/SUP], Lingling Wang[SUP] 1 [/SUP], Ao Wen[SUP] 1 [/SUP], Yanping Duan[SUP] 1 [/SUP], Xindan Zhang[SUP] 1 [/SUP], Yushan Dai[SUP] 1 [/SUP], Keqing Yin[SUP] 1 [/SUP], Xin Yuan[SUP] 1 [/SUP], Chongzhang Yu[SUP] 1 [/SUP], Bin He[SUP] 1 [/SUP], Yu Cao[SUP] 1 2 [/SUP], Haohao Dong[SUP] 3 [/SUP], Jian Li[SUP] 4 [/SUP], Qi Zhao[SUP] 5 [/SUP], Guangwen Lu[SUP] 1 [/SUP]
Affiliations
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.
. 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[SUP] 1 [/SUP], Liyan Guo[SUP] 1 [/SUP], Sheng Lin[SUP] 1 [/SUP], Zimin Chen[SUP] 1 [/SUP], Fanli Yang[SUP] 1 [/SUP], Jing Yang[SUP] 1 [/SUP], Lingling Wang[SUP] 1 [/SUP], Ao Wen[SUP] 1 [/SUP], Yanping Duan[SUP] 1 [/SUP], Xindan Zhang[SUP] 1 [/SUP], Yushan Dai[SUP] 1 [/SUP], Keqing Yin[SUP] 1 [/SUP], Xin Yuan[SUP] 1 [/SUP], Chongzhang Yu[SUP] 1 [/SUP], Bin He[SUP] 1 [/SUP], Yu Cao[SUP] 1 2 [/SUP], Haohao Dong[SUP] 3 [/SUP], Jian Li[SUP] 4 [/SUP], Qi Zhao[SUP] 5 [/SUP], Guangwen Lu[SUP] 1 [/SUP]
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.