Intranasal administration of broad-spectrum macrocyclic peptide inhibitor protects against SARS-CoV-2 Omicron variants

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.

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Publication Details

Journal
Nature Communications
Published
2026-01-26
DOI
https://doi.org/10.1038/s41467-026-68462-9
Citations
1
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
32.78
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article

Intranasal administration of broad-spectrum macrocyclic peptide inhibitor protects against SARS-CoV-2 Omicron variants

Yubin Xie, Yizhen Yin, Yahong Tan, Jasper Fuk‐Woo Chan et al.
1 citations
Nature Communications
SARS-CoV-2 and COVID-19 Research
32.78
article

Intranasal administration of broad-spectrum macrocyclic peptide inhibitor protects against SARS-CoV-2 Omicron variants

Yubin Xie, Yizhen Yin, Yahong Tan, Jasper Fuk‐Woo Chan, Guoli Shi, Yongqi Li, Yong Chen, Hao Luo, Youming Zhang, Jinyue Yang, Junhua Li, Hongwei Hou, Shuofeng Yuan, Yaning Fu, Yang Yang, Qi Peng, Yi Shi, Anna Jinxia Zhang, George Fu Gao, Vincent Kwok-Man Poon, Chris Chung-Sing Chan, Alex A. Compton, Na Xiao, Min Wang
article en
1 citations

Abstract

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.

Nature CommunicationsVol. 17(1)
Ningbo University (CN), Qingdao University of Science and Technology (CN), Shandong University (CN), Hong Kong Science and Technology Parks Corporation (HK), First Affiliated Hospital of Guangzhou Medical University (CN), Institute of Microbiology (BY), Guangzhou Automobile Group (China) (CN), Czech Academy of Sciences, Institute of Microbiology (CZ), Institute of Microbiology (CN), National Cancer Institute (US), University of Hong Kong - Shenzhen Hospital (CN), Center for Cancer Research (US), Beijing Academy of Science and Technology (CN), University of Chinese Academy of Sciences (CN), Shenzhen Third People’s Hospital (CN), China Agricultural University (CN), University of Hong Kong (HK), Guangzhou Medical University (CN)
Good health and well-being
Openalex Percentile: Top 1%
SARS-CoV-2 and COVID-19 Research
32.78
DOIOpen Access PDFOpenAlex
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