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TitleIntranasal administration of broad-spectrum macrocyclic peptide inhibitor protects against SARS-CoV-2 Omicron variants.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Page 1753, Year 2026
Publish dateJan 26, 2026
AuthorsMin Wang / Jinyue Yang / Yahong Tan / Shuofeng Yuan / Guoli Shi / Qi Peng / Yongqi Li / Vincent Kwok-Man Poon / Chris Chung-Sing Chan / Na Xiao / Anna Jinxia Zhang / Yubin Xie / Junhua Li / Hao Luo / Yaning Fu / Yong Chen / Alex A Compton / Youming Zhang / Yang Yang / George Fu Gao / Hongwei Hou / Jasper Fuk-Woo Chan / Yizhen Yin / Yi Shi /
PubMed AbstractSevere 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 ...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.
External linksNat Commun / PubMed:41587975 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.4 Å
Structure data

62786

9l3i

EMDB-62786, PDB-9l3i:
Cryo-EM structure of SARS-CoV-2 BA.2.75 Spike Protein complex with a potent broad-spectrum macrocyclic peptide inhibitor 6L3-3P11K
Method: EM (single particle) / Resolution: 3.1 Å

62788

9l3q

EMDB-62788, PDB-9l3q:
Cryo-EM structure of SARS-CoV-2 PT Spike Protein complex with a potent broad-spectrum macrocyclic peptide inhibitor 6L3-3P11K
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-67440: Cryo-EM map of SARS-CoV-2 BA.2.75 Spike Protein complex with macrocyclic peptide 6L3 (All RBDs up)
Method: EM (single particle) / Resolution: 3.25 Å

EMDB-67548: Cryo-EM map of SARS-CoV-2 BA.2.75 Spike Protein complex with a macrocyclic peptide 6L3-3P11K (Two RBDs up)
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-67549: Cryo-EM map of SARS-CoV-2 PT Spike Protein,Three RBDs down
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-67568: Cryo-EM map of SARS-CoV-2 BA.2.75 Spike Protein (Three RBDs down)
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • severe acute respiratory syndrome coronavirus 2
  • synthetic construct (others)
  • Severe acute respiratory syndrome coronavirus
KeywordsVIRAL PROTEIN / Complex / Inhibitor / Complex.

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