Tweet
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 # 1 2 3 , Jinyue Yang # 4 , Yahong Tan # 5 , Shuofeng Yuan # 6 7 , Guoli Shi # 8 , Qi Peng 1 2 3 9 , Yongqi Li 3 , Vincent Kwok-Man Poon 6 7 , Chris Chung-Sing Chan 6 7 , Na Xiao 6 7 , Anna Jinxia Zhang 6 7 , Yubin Xie 6 7 , Junhua Li 2 , Hao Luo 5 , Yaning Fu 1 , Yong Chen 1 , Alex A Compton 8 , Youming Zhang 5 , Yang Yang 10 , George Fu Gao 1 2 3 11 , Hongwei Hou 12 , Jasper Fuk-Woo Chan 13 14 15 16 , Yizhen Yin 17 , Yi Shi 18 19 20 21 22
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 # 1 2 3 , Jinyue Yang # 4 , Yahong Tan # 5 , Shuofeng Yuan # 6 7 , Guoli Shi # 8 , Qi Peng 1 2 3 9 , Yongqi Li 3 , Vincent Kwok-Man Poon 6 7 , Chris Chung-Sing Chan 6 7 , Na Xiao 6 7 , Anna Jinxia Zhang 6 7 , Yubin Xie 6 7 , Junhua Li 2 , Hao Luo 5 , Yaning Fu 1 , Yong Chen 1 , Alex A Compton 8 , Youming Zhang 5 , Yang Yang 10 , George Fu Gao 1 2 3 11 , Hongwei Hou 12 , Jasper Fuk-Woo Chan 13 14 15 16 , Yizhen Yin 17 , Yi Shi 18 19 20 21 22
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.