Structural biology of Nipah virus G and F glycoproteins: Insights into therapeutic and vaccine development

Abstract

Nipah virus (NiV), a highly pathogenic zoonotic paramyxovirus, poses a significant public health threat due to its high mortality rate and potential for human-to-human transmission. The attachment (G) and fusion (F) glycoproteins play pivotal roles in viral entry and host-cell fusion, making them prime targets for therapeutic and vaccine development. Recent advances in structural biology have provided high-resolution insights into the molecular architecture and functional dynamics of these glycoproteins, revealing key epitopes and domains essential for neutralizing antibody responses. The G glycoprotein's head domain and the prefusion F ectodomain have emerged as focal points for vaccine design, with multivalent display strategies showing promise in enhancing immunogenicity and breadth of protection. Structural studies have also informed the development of monoclonal antibodies like m102.4, offering potential post-exposure therapies. Additionally, insights from cryo-electron microscopy and X-ray crystallography have facilitated the design of structure-based inhibitors and next-generation vaccines, including nanoparticle and multi-epitope formulations. This review highlights recent structural findings on the NiV G and F glycoproteins, their implications for therapeutic strategies, and the challenges in developing effective and targeted interventions. A deeper understanding of these glycoproteins will be crucial for advancing NiV-specific therapeutics and vaccines, ultimately enhancing global preparedness against future outbreaks.

Keywords: Nipah virus; attachment glycoprotein; fusion glycoprotein; therapeutic; vaccine.

Fig. 1.

Structures of the henipavirus G glycoprotein complex with ephrin-B2, m102, and nAH1.3. a) Ephrin-B2 (orange) binds to the NiV G glycoprotein (gray) mainly via its G-H loop (residues 107–125) that is inserted into a central depression in the upper surface of the G glycoprotein β-propeller. F120 of ephrin-B2 is deeply buried within a pocket and interacts with Q559, E579, I580, Y581, and I588 of the G glycoprotein, and is crucial for binding. Similarly, L124 and W125 of ephrin-B2 are essential for NiV-G binding, engaging with a highly hydrophobic surface of NiV-G that includes W504, F458, and L305 (PDB ID: 2VSM) [16]. b) m102.3 Fab binds to the hydrophobic central cavity of the HeV G glycoprotein (gray) via its complementarity determining region (CDR)-3 of the heavy chain (green) in a similar angle and from the same direction as the G-H loop of ephrin-B2. Among the eight residues at the tip of CDR-H3 of m102.3, L105 is surrounded by Q559, A532, N557, Y581, I580, I588, and E579 of HeV-G; P107 interacts with T530, A532, P488, T507, and Q490 of HeV-G; P109 is in proximity to E505, W504, and Y458 of HeV-G; S110 is surrounded by L305 and W504 of HeV-G; and Y122 is enclosed by T241, C240, T218, S239, and E579 of HeV-G (PDB ID: 6CMG) [20]. c) Unlike the ephrin-B2 binding, nAH1.3 binds to a discontinuous epitope at the opposite side of the β-propeller. The interacting nAH1.3 heavy and light chains CDRs (CDRH and CDRL) rendered in green and cyan, respectively (PDB ID: 7TXZ) [18]. The structural visualization was generated using PyMOL (Schrödinger, New York, USA)

Fig. 2.

Structures of the NiV F glycoprotein in its prefusion state and complex with mAb66. a) The prefusion F glycoprotein adopts a tree-like shape with three copies of the glycoprotein arranged around a central axis. The fusion peptide (residues 110–122), within the N-terminal segment, is colored in magenta, with the cathepsin-L cleavage site (R109–L110), which is easily accessible for cleavage, is labelled (PDB ID: 5EVM) [31]. b) Crystal structure of the NiV F glycoprotein (gray) complex with mAb66. The heavy and light chains are shown in green and cyan, respectively. The structure shows that each mAb66 molecule binds to an epitope near the apex of a single prefusion F protomer in the trimer. The interaction is predominantly mediated by CDR L3 of mAb66 that targets the epitope within domain III of the NiV F glycoprotein, primarily interacting with residues K60–K80 (shown in yellow). I95A on CDR L3, the most buried residue in the complex, is shown. Other interacting residues are Y92, Y93, and Y95C (PDB ID: 6T3F) [36]. The structural visualization was generated using PyMOL (Schrödinger, New York, USA)