Peptide–Ligand Conjugate‐Based Immunotherapeutic Strategy Targeting Nipah Virus Glycoprotein G: A Novel Approach for Treating Virus Infection by Employing Host Innate Immune Response

Since birth, the human immune system continuously adapts to environmental exposures, developing robust immunological memory against a diverse range of antigens and allergens. Leveraging this pre-existing immunity, this study introduces a novel immunotherapeutic approach targeting the Nipah virus, a zoonotic pathogen with a high mortality rate and no approved vaccines or therapeutics to date. The NiV glycoprotein G (NiV-G), essential for viral attachment and fusion with host cells, was identified as a prime therapeutic target. This study proposes a peptide ligand complex (PLC) that constitutes high-affinity ligands of NiV-G joined with immunogenic peptides for stronger host innate immune response by an oxime linker using high-throughput virtual screening (HTVS) and molecular dynamics simulations, Bleomycin and Octreotide were selected as potent ligands for NiV-G. These were conjugated via an oxime linker to peptides derived from Escherichia coli outer membrane proteins (OMPs), which exploit the natural antibody memory against E. coli , constituting approximately 0.057% of total serum immunoglobulins in healthy individuals. The ligand component of PLC binds specifically to NiV-G, blocking viral entry, fusion, and preventing syncytia formation, an essential mechanism for cell-to-cell spread. Simultaneously, the peptide component activates immune effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), promoting the clearance of infected cells and free viral particles from circulation. Computational analyses confirmed the Safety, stability, and immunogenicity of the PLC components. This strategy presents a compelling alternative to conventional monoclonal antibody-based therapies, which are often constrained by high production costs, storage limitations, restricted accessibility, and susceptibility to antigenic drift. By harnessing pre-existing immune memory and redirecting it toward viral targets, the peptide ligand complex (PLC) offers a cost-effective and adaptable therapeutic platform. Beyond addressing the challenges posed by Nipah virus, this approach holds potential for combating other hard-to-treat infectious diseases and even cancer by transforming natural immunity into a powerful and versatile tool for targeted immunotherapy.