tetano
Editor, Senior Moderator
PLoS Pathog
. 2025 Apr 11;21(4):e1013034.
doi: 10.1371/journal.ppat.1013034. Online ahead of print. Structural basis and mode of action for two broadly neutralizing nanobodies targeting the highly conserved spike stem-helix of sarbecoviruses including SARS-CoV-2 and its variants
Liyan Guo[SUP] 1 2 [/SUP], Zimin Chen[SUP] 1 [/SUP], Sheng Lin[SUP] 1 [/SUP], Fanli Yang[SUP] 1 [/SUP], Jing Yang[SUP] 1 [/SUP], Lingling Wang[SUP] 1 [/SUP], Xindan Zhang[SUP] 1 [/SUP], Xin Yuan[SUP] 1 [/SUP], Bin He[SUP] 1 [/SUP], Yu Cao[SUP] 1 3 [/SUP], Jian Li[SUP] 4 [/SUP], Qi Zhao[SUP] 5 [/SUP], Guangwen Lu[SUP] 1 [/SUP]
Affiliations
The persistent emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlights the need for developing broad-spectrum antiviral agents. Here, we report the identification of two sarbecovirus S2-specific alpaca nanobodies, namely H17 and H145, that effectively neutralize known SARS-CoV-2 variants (including the Omicron subvariants) and other sarbecoviruses (such as SARS-CoV, PANG/GD, WIV1, and HKU3). The two nanobodies recognize a linear epitope (D1139PLQPELDSFKEEL1152) in the upper region of the S2 stem-helix (SH), which is highly conserved among SARS-CoV-2 variants and other sarbecoviruses. The complex structure of the nanobody bound to the epitope SH-peptide reveal that nanobody binding will impede the refolding of S2, effectively neutralizing the virus. Moreover, the nanobodies bind viral S2 in an acidification-insensitive manner, demonstrating their capacity for entry inhibition especially when viruses enter via the endosomal route. Finally, H17 and H145 possess a better taking-action window for virus neutralization, superior to the RBD-targeting nanobodies that exert neutralization by competing against ACE2 binding. Taken together, the results suggest that anti-SH nanobodies H17 and H145 are promising broad-spectrum drug candidates for preventing and treating the pandemic infections by SARS-CoV-2 variants and other sarbecoviruses.
. 2025 Apr 11;21(4):e1013034.
doi: 10.1371/journal.ppat.1013034. Online ahead of print. Structural basis and mode of action for two broadly neutralizing nanobodies targeting the highly conserved spike stem-helix of sarbecoviruses including SARS-CoV-2 and its variants
Liyan Guo[SUP] 1 2 [/SUP], Zimin Chen[SUP] 1 [/SUP], Sheng Lin[SUP] 1 [/SUP], Fanli Yang[SUP] 1 [/SUP], Jing Yang[SUP] 1 [/SUP], Lingling Wang[SUP] 1 [/SUP], Xindan Zhang[SUP] 1 [/SUP], Xin Yuan[SUP] 1 [/SUP], Bin He[SUP] 1 [/SUP], Yu Cao[SUP] 1 3 [/SUP], Jian Li[SUP] 4 [/SUP], Qi Zhao[SUP] 5 [/SUP], Guangwen Lu[SUP] 1 [/SUP]
Affiliations
- PMID: 40215243
- DOI: 10.1371/journal.ppat.1013034
The persistent emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlights the need for developing broad-spectrum antiviral agents. Here, we report the identification of two sarbecovirus S2-specific alpaca nanobodies, namely H17 and H145, that effectively neutralize known SARS-CoV-2 variants (including the Omicron subvariants) and other sarbecoviruses (such as SARS-CoV, PANG/GD, WIV1, and HKU3). The two nanobodies recognize a linear epitope (D1139PLQPELDSFKEEL1152) in the upper region of the S2 stem-helix (SH), which is highly conserved among SARS-CoV-2 variants and other sarbecoviruses. The complex structure of the nanobody bound to the epitope SH-peptide reveal that nanobody binding will impede the refolding of S2, effectively neutralizing the virus. Moreover, the nanobodies bind viral S2 in an acidification-insensitive manner, demonstrating their capacity for entry inhibition especially when viruses enter via the endosomal route. Finally, H17 and H145 possess a better taking-action window for virus neutralization, superior to the RBD-targeting nanobodies that exert neutralization by competing against ACE2 binding. Taken together, the results suggest that anti-SH nanobodies H17 and H145 are promising broad-spectrum drug candidates for preventing and treating the pandemic infections by SARS-CoV-2 variants and other sarbecoviruses.