Structural definition of a neutralization epitope on the N-terminal domain of MERS-CoV spike glycoprotein

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Neutralizing antibodies against Middle East respiratory syndrome coronavirus (MERS-CoV) primarily target the spike glycoprotein's receptor-binding domain (RBD).
• The mechanisms and epitopes of antibodies targeting non-RBD regions of the MERS-CoV spike remain less understood.

Purpose of the Study:

• To characterize a novel monoclonal antibody (mAb) 7D10 that targets the N-terminal domain (NTD) of the MERS-CoV spike glycoprotein.
• To elucidate the epitope and neutralization mechanism of mAb 7D10.

Main Methods:

• Structure determination and mutagenesis experiments to identify the epitope and critical residues for antibody binding.
• In vitro assays to assess viral entry inhibition and neutralization breadth.
• Analysis of antibody mechanism, including effects on receptor binding and viral conformational changes.

Main Results:

• mAb 7D10 binds to the NTD of the MERS-CoV spike glycoprotein and potently inhibits viral cell entry.
• The epitope and key NTD residues for 7D10 binding and neutralization were identified.
• Neutralization by 7D10 is not solely dependent on blocking DPP4 binding but also inhibits post-attachment conformational changes of the spike protein.
• 7D10 exhibits broad neutralization and synergistic effects with RBD-targeting antibodies.

Conclusions:

• mAb 7D10 represents a potent neutralizing antibody targeting the MERS-CoV spike NTD.
• Its mechanism involves inhibiting viral conformational changes post-attachment, contributing to its broad efficacy.
• 7D10 holds potential for MERS-CoV therapeutic strategies, possibly in combination with other antibodies.