tetano
Editor, Senior Moderator
Cell Rep Med
. 2024 Feb 3:101418.
doi: 10.1016/j.xcrm.2024.101418. Online ahead of print. An enhanced broad-spectrum peptide inhibits Omicron variants in vivo
Wenwen Bi[SUP] 1 [/SUP], Kaiming Tang[SUP] 2 [/SUP], Guilin Chen[SUP] 3 [/SUP], Yubin Xie[SUP] 2 [/SUP], Nicholas F Polizzi[SUP] 4 [/SUP], William F DeGrado[SUP] 5 [/SUP], Shuofeng Yuan[SUP] 6 [/SUP], Bobo Dang[SUP] 7 [/SUP]
Affiliations
The continual emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) poses a major challenge to vaccines and antiviral therapeutics due to their extensive evasion of immunity. Aiming to develop potent and broad-spectrum anticoronavirus inhibitors, we generated A1-(GGGGS)7-HR2m (A1L35HR2m) by introducing an angiotensin-converting enzyme 2 (ACE2)-derived peptide A1 to the N terminus of the viral HR2-derived peptide HR2m through a long flexible linker, which showed significantly improved antiviral activity. Further cholesterol (Chol) modification at the C terminus of A1L35HR2m greatly enhanced the inhibitory activities against SARS-CoV-2, SARS-CoV-2 VOCs, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) pseudoviruses, with IC[SUB]50[/SUB] values ranging from 0.16 to 5.53 nM. A1L35HR2m-Chol also potently inhibits spike-protein-mediated cell-cell fusion and the replication of authentic Omicron BA.2.12.1, BA.5, and EG.5.1. Importantly, A1L35HR2m-Chol distributed widely in respiratory tract tissue and had a long half-life (>10 h) in vivo. Intranasal administration of A1L35HR2m-Chol to K18-hACE2 transgenic mice potently inhibited Omicron BA.5 and EG.5.1 infection both prophylactically and therapeutically.
Keywords: ACE2 peptide; HR2 peptide; SARS-CoV-2; cholesterol modification; lipopeptide; pan-coronavirus fusion inhibitor; synergistic effect; variants of concern.
. 2024 Feb 3:101418.
doi: 10.1016/j.xcrm.2024.101418. Online ahead of print. An enhanced broad-spectrum peptide inhibits Omicron variants in vivo
Wenwen Bi[SUP] 1 [/SUP], Kaiming Tang[SUP] 2 [/SUP], Guilin Chen[SUP] 3 [/SUP], Yubin Xie[SUP] 2 [/SUP], Nicholas F Polizzi[SUP] 4 [/SUP], William F DeGrado[SUP] 5 [/SUP], Shuofeng Yuan[SUP] 6 [/SUP], Bobo Dang[SUP] 7 [/SUP]
Affiliations
- PMID: 38340726
- DOI: 10.1016/j.xcrm.2024.101418
The continual emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) poses a major challenge to vaccines and antiviral therapeutics due to their extensive evasion of immunity. Aiming to develop potent and broad-spectrum anticoronavirus inhibitors, we generated A1-(GGGGS)7-HR2m (A1L35HR2m) by introducing an angiotensin-converting enzyme 2 (ACE2)-derived peptide A1 to the N terminus of the viral HR2-derived peptide HR2m through a long flexible linker, which showed significantly improved antiviral activity. Further cholesterol (Chol) modification at the C terminus of A1L35HR2m greatly enhanced the inhibitory activities against SARS-CoV-2, SARS-CoV-2 VOCs, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) pseudoviruses, with IC[SUB]50[/SUB] values ranging from 0.16 to 5.53 nM. A1L35HR2m-Chol also potently inhibits spike-protein-mediated cell-cell fusion and the replication of authentic Omicron BA.2.12.1, BA.5, and EG.5.1. Importantly, A1L35HR2m-Chol distributed widely in respiratory tract tissue and had a long half-life (>10 h) in vivo. Intranasal administration of A1L35HR2m-Chol to K18-hACE2 transgenic mice potently inhibited Omicron BA.5 and EG.5.1 infection both prophylactically and therapeutically.
Keywords: ACE2 peptide; HR2 peptide; SARS-CoV-2; cholesterol modification; lipopeptide; pan-coronavirus fusion inhibitor; synergistic effect; variants of concern.