9L3Q

Cryo-EM structure of SARS-CoV-2 PT Spike Protein complex with a potent broad-spectrum macrocyclic peptide inhibitor 6L3-3P11K

Summary for 9L3Q

• Entry DOI: 10.2210/pdb9l3q/pdb
• EMDB information: 62788
• Descriptor: Spike glycoprotein, TYR-ASP-PRO-28J-LEU-THR-PRO-LEU-GLY-PHE-LYS-CCS-GLY-NH2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: inhibitor, complex., viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 6
• Total formula weight: 412678.18

Authors

Wang, M.,Yang, J.Y.,Peng, Q.,Shi, Y. (deposition date: 2024-12-19, release date: 2026-03-11)

Primary citation

Wang, M.,Yang, J.,Tan, Y.,Yuan, S.,Shi, G.,Peng, Q.,Li, Y.,Poon, V.K.,Chan, C.C.,Xiao, N.,Zhang, A.J.,Xie, Y.,Li, J.,Luo, H.,Fu, Y.,Chen, Y.,Compton, A.A.,Zhang, Y.,Yang, Y.,Gao, G.F.,Hou, H.,Chan, J.F.,Yin, Y.,Shi, Y.
Intranasal administration of broad-spectrum macrocyclic peptide inhibitor protects against SARS-CoV-2 Omicron variants.
Nat Commun, 17:1753-1753, 2026

PubMed 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.

PubMed: 41587975
DOI: 10.1038/s41467-026-68462-9

Experimental method

ELECTRON MICROSCOPY (2.7 Å)