7C53

Crystal Structure of SARS-CoV-2 HR1 motif in complex with pan-CoVs inhibitor EK1

Summary for 7C53

• Entry DOI: 10.2210/pdb7c53/pdb
• Descriptor: Spike protein S2',pan-CoVs inhibitor EK1, CALCIUM ION (3 entities in total)
• Functional Keywords: sars-cov-2 hr1, pan-covs inhibitor, ek1 peptide, virus, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV); More
• Total number of polymer chains: 6
• Total formula weight: 70040.53

Authors

Zhu, Y.,Yang, X.,Sun, F. (deposition date: 2020-05-19, release date: 2021-05-19, Last modification date: 2023-11-29)

Primary citation

Xia, S.,Lan, Q.,Zhu, Y.,Wang, C.,Xu, W.,Li, Y.,Wang, L.,Jiao, F.,Zhou, J.,Hua, C.,Wang, Q.,Cai, X.,Wu, Y.,Gao, J.,Liu, H.,Sun, G.,Munch, J.,Kirchhoff, F.,Yuan, Z.,Xie, Y.,Sun, F.,Jiang, S.,Lu, L.
Structural and functional basis for pan-CoV fusion inhibitors against SARS-CoV-2 and its variants with preclinical evaluation.
Signal Transduct Target Ther, 6:288-288, 2021

PubMed Abstract: The COVID-19 pandemic poses a global threat to public health and economy. The continuously emerging SARS-CoV-2 variants present a major challenge to the development of antiviral agents and vaccines. In this study, we identified that EK1 and cholesterol-coupled derivative of EK1, EK1C4, as pan-CoV fusion inhibitors, exhibit potent antiviral activity against SARS-CoV-2 infection in both lung- and intestine-derived cell lines (Calu-3 and Caco2, respectively). They are also effective against infection of pseudotyped SARS-CoV-2 variants B.1.1.7 (Alpha) and B.1.1.248 (Gamma) as well as those with mutations in S protein, including N417T, E484K, N501Y, and D614G, which are common in South African and Brazilian variants. Crystal structure revealed that EK1 targets the HR1 domain in the SARS-CoV-2 S protein to block virus-cell fusion and provide mechanistic insights into its broad and effective antiviral activity. Nasal administration of EK1 peptides to hACE2 transgenic mice significantly reduced viral titers in lung and intestinal tissues. EK1 showed good safety profiles in various animal models, supporting further clinical development of EK1-based pan-CoV fusion inhibitors against SARS-CoV-2 and its variants.

PubMed: 34326308
DOI: 10.1038/s41392-021-00712-2

Experimental method

X-RAY DIFFRACTION (2.278 Å)