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Abstract
Nipah Virus (NiV) has been designated as a priority disease with an urgent need for therapeutic development by World Health Organization. The monoclonal antibody m102.4 binds to the immunodominant NiV receptor-binding glycoprotein (GP), and potently neutralizes NiV, indicating its potential as a therapeutic agent. Although the co-crystal structure of m102.3, an m102.4 derivative, in complex with the GP of the related Hendra Virus (HeV) has been solved, the structural interaction between m102.4 and NiV is uncharacterized. Herein, we used structure-guided alanine-scanning mutagenesis to map the functional epitope and paratope residues that govern the antigen–antibody interaction. Our results revealed that the binding of m102.4 is mediated predominantly by two residues in the HCDR3 region, which is unusually small for an antibody-antigen interaction. We performed computational docking to generate a structural model of m102.4-NiV interaction. Our model indicates that m102.4 targets the common hydrophobic central cavity and a hydrophilic rim on the GP, as observed for the m102.3-HeV co-crystal, albeit with Fv orientation differences. In summary, our study provides insight into the m102.4-NiV interaction, demonstrating that structure-guided alanine-scanning and computational modeling can serve as the starting point for additional antibody reengineering (e.g. affinity maturation) to generate potential therapeutic candidates.
Highlights
Nipah Virus (NiV) has been designated as a priority disease with an urgent need for therapeutic development by World Health Organization
The membrane anchored GP of NiV is responsible for viral attachment through a protein–protein dominated interaction with the Ephrin-B2/B3 human host cell receptor in which the tip of the G-H loop on the Ephrin fits into a hydrophobic central cavity in the GP15
In order to elucidate the critical hotspots contributing to m102.4′s binding to NiV GP, we performed a structure-guided alanine scanning of epitope and paratope residues
Summary
Nipah Virus (NiV) has been designated as a priority disease with an urgent need for therapeutic development by World Health Organization. The monoclonal antibody m102.4 binds to the immunodominant NiV receptor-binding glycoprotein (GP), and potently neutralizes NiV, indicating its potential as a therapeutic agent. Our study provides insight into the m102.4-NiV interaction, demonstrating that structure-guided alanine-scanning and computational modeling can serve as the starting point for additional antibody reengineering (e.g. affinity maturation) to generate potential therapeutic candidates. Unpredictability, potential for large-scale outbreaks, and propensity for developing resistance have led Nipah and Henipaviral diseases to be deemed as one of 10 Blueprint Priority Diseases in urgent need of R&D by the World Health O rganization[16]. Developing a monoclonal antibody against NiV is an ideal solution because administration of the mAb to infected patients and at-risk populations could potentially prevent new infections, treat existing infections, and contain an outbreak
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