tetano
Editor, Senior Moderator
Nat Commun
. 2026 Jan 26.
doi: 10.1038/s41467-026-68462-9. Online ahead of print.
Intranasal administration of broad-spectrum macrocyclic peptide inhibitor protects against SARS-CoV-2 Omicron variants
Min Wang[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Jinyue Yang[SUP] #[/SUP][SUP] 4 [/SUP], Yahong Tan[SUP] #[/SUP][SUP] 5 [/SUP], Shuofeng Yuan[SUP] #[/SUP][SUP] 6 7 [/SUP], Guoli Shi[SUP] #[/SUP][SUP] 8 [/SUP], Qi Peng[SUP] 1 2 3 9 [/SUP], Yongqi Li[SUP] 3 [/SUP], Vincent Kwok-Man Poon[SUP] 6 7 [/SUP], Chris Chung-Sing Chan[SUP] 6 7 [/SUP], Na Xiao[SUP] 6 7 [/SUP], Anna Jinxia Zhang[SUP] 6 7 [/SUP], Yubin Xie[SUP] 6 7 [/SUP], Junhua Li[SUP] 2 [/SUP], Hao Luo[SUP] 5 [/SUP], Yaning Fu[SUP] 1 [/SUP], Yong Chen[SUP] 1 [/SUP], Alex A Compton[SUP] 8 [/SUP], Youming Zhang[SUP] 5 [/SUP], Yang Yang[SUP] 10 [/SUP], George Fu Gao[SUP] 1 2 3 11 [/SUP], Hongwei Hou[SUP] 12 [/SUP], Jasper Fuk-Woo Chan[SUP] 13 14 15 16 [/SUP], Yizhen Yin[SUP] 17 [/SUP], Yi Shi[SUP] 18 19 20 21 22 [/SUP]
Affiliations
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to cause significant morbidity and mortality despite the end of its pandemic phase. The emergence of highly mutated SARS-CoV-2 variants of concern highlights the requirement of broad-spectrum antiviral countermeasures which possess both prophylactic and therapeutic efficacies. Here, we obtain a macrocyclic peptide, 6L3-3P11K, that effectively inhibits a wide range of SARS-CoV-2 variants and subvariants. Structural studies show that 6L3-3P11K forms homotrimers that lock the spike protein (S) trimer into a "closed" conformation by engaging a conserved non-receptor binding motif (non-RBM) of S. This interaction disrupts the binding between S and ACE2 receptor. Structure-guided modifications result in a thermostable and trypsin-resistant macrocyclic peptide, 6L3-1F3P11hR, that exhibits prophylactic and therapeutic effects against SARS-CoV-2 infection in a male hACE2 transgenic mouse model after intranasal administration. Our results provide a drug candidate for the control and prevention of COVID-19 and may stimulate further research on macrocyclic broad-spectrum anti-coronavirus drug development.
. 2026 Jan 26.
doi: 10.1038/s41467-026-68462-9. Online ahead of print.
Intranasal administration of broad-spectrum macrocyclic peptide inhibitor protects against SARS-CoV-2 Omicron variants
Min Wang[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Jinyue Yang[SUP] #[/SUP][SUP] 4 [/SUP], Yahong Tan[SUP] #[/SUP][SUP] 5 [/SUP], Shuofeng Yuan[SUP] #[/SUP][SUP] 6 7 [/SUP], Guoli Shi[SUP] #[/SUP][SUP] 8 [/SUP], Qi Peng[SUP] 1 2 3 9 [/SUP], Yongqi Li[SUP] 3 [/SUP], Vincent Kwok-Man Poon[SUP] 6 7 [/SUP], Chris Chung-Sing Chan[SUP] 6 7 [/SUP], Na Xiao[SUP] 6 7 [/SUP], Anna Jinxia Zhang[SUP] 6 7 [/SUP], Yubin Xie[SUP] 6 7 [/SUP], Junhua Li[SUP] 2 [/SUP], Hao Luo[SUP] 5 [/SUP], Yaning Fu[SUP] 1 [/SUP], Yong Chen[SUP] 1 [/SUP], Alex A Compton[SUP] 8 [/SUP], Youming Zhang[SUP] 5 [/SUP], Yang Yang[SUP] 10 [/SUP], George Fu Gao[SUP] 1 2 3 11 [/SUP], Hongwei Hou[SUP] 12 [/SUP], Jasper Fuk-Woo Chan[SUP] 13 14 15 16 [/SUP], Yizhen Yin[SUP] 17 [/SUP], Yi Shi[SUP] 18 19 20 21 22 [/SUP]
Affiliations
- PMID: 41587975
- DOI: 10.1038/s41467-026-68462-9
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to cause significant morbidity and mortality despite the end of its pandemic phase. The emergence of highly mutated SARS-CoV-2 variants of concern highlights the requirement of broad-spectrum antiviral countermeasures which possess both prophylactic and therapeutic efficacies. Here, we obtain a macrocyclic peptide, 6L3-3P11K, that effectively inhibits a wide range of SARS-CoV-2 variants and subvariants. Structural studies show that 6L3-3P11K forms homotrimers that lock the spike protein (S) trimer into a "closed" conformation by engaging a conserved non-receptor binding motif (non-RBM) of S. This interaction disrupts the binding between S and ACE2 receptor. Structure-guided modifications result in a thermostable and trypsin-resistant macrocyclic peptide, 6L3-1F3P11hR, that exhibits prophylactic and therapeutic effects against SARS-CoV-2 infection in a male hACE2 transgenic mouse model after intranasal administration. Our results provide a drug candidate for the control and prevention of COVID-19 and may stimulate further research on macrocyclic broad-spectrum anti-coronavirus drug development.