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Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor
11] Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai 200032, China [2].
Abstract:
A novel human coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), has caused outbreaks of a SARS-like illness with high case fatality rate. The reports of its person-to-person transmission through close contacts have raised a global concern about its pandemic potential. Here we characterize the six-helix bundle fusion core structure of MERS-CoV spike protein S2 subunit by X-ray crystallography and biophysical analysis. We find that two peptides, HR1P and HR2P, spanning residues 998-1039 in HR1 and 1251-1286 in HR2 domains, respectively, can form a stable six-helix bundle fusion core structure, suggesting that MERS-CoV enters into the host cell mainly through membrane fusion mechanism. HR2P can effectively inhibit MERS-CoV replication and its spike protein-mediated cell-cell fusion. Introduction of hydrophilic residues into HR2P results in significant improvement of its stability, solubility and antiviral activity. Therefore, the HR2P analogues have good potential to be further developed into effective viral fusion inhibitors for treating MERS-CoV infection.
Insights
Researchers studied the Middle East respiratory syndrome coronavirus (MERS-CoV) fusion core. They found a peptide (HR2P) that inhibits MERS-CoV replication and shows potential as an antiviral drug.
Area of Science:
- Structural Biology
- Virology
- Drug Discovery
Background:
- Middle East respiratory syndrome coronavirus (MERS-CoV) outbreaks present a significant public health concern due to high fatality rates and potential for person-to-person transmission.
- Understanding the MERS-CoV entry mechanism is crucial for developing effective antiviral therapies.
Purpose of the Study:
- To characterize the six-helix bundle fusion core structure of the MERS-CoV spike protein S2 subunit.
- To investigate the potential of peptides derived from the fusion core as antiviral agents against MERS-CoV.
Main Methods:
- X-ray crystallography was employed to determine the structure of the MERS-CoV spike protein S2 subunit's fusion core.
- Biophysical analysis was conducted to assess the stability and function of identified peptides.
- Antiviral activity was evaluated by measuring inhibition of MERS-CoV replication and spike protein-mediated cell-cell fusion.
Main Results:
- A stable six-helix bundle fusion core structure was formed by two peptides, HR1P and HR2P, from the MERS-CoV spike protein S2 subunit.
- The HR2P peptide demonstrated significant inhibition of MERS-CoV replication and cell-cell fusion.
- Modification of HR2P with hydrophilic residues enhanced its stability, solubility, and antiviral efficacy.
Conclusions:
- MERS-CoV likely enters host cells via a membrane fusion mechanism, involving the formation of a six-helix bundle.
- HR2P analogues represent promising candidates for developing novel antiviral fusion inhibitors to treat MERS-CoV infections.
