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

ABSTRACT 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.