Development and optimization of a peptide inhibitor of influenza virus splicing for broad-spectrum antiviral therapy

PROJECT SUMMARY: In this grant proposal, we aim to develop the L7Ae protein as a therapeutic for treating Orthomyxoviridae family infections. Our approach includes three aims: (1) Investigating the mechanism of action of L7Ae on various family members, focusing on its interaction with the conserved k-turn recognition domain in the L30 RNA- binding proteins, to identify key viral targets and understand how L7Ae disrupts the viral life cycle. (2) Characterizing a recently developed L7Ae transgenic mouse model that shows normal development but resistance to influenza A virus, providing an independent platform to study L7Ae's effects on host and virus biology. (3) Assessing the administration of recombinant L7Ae in vivo by introducing it into mouse lungs and evaluating lung function parameters and histological analyses to examine its impact on lung morphology and inflammation, thereby evaluating potential adverse effects on the host. Our ultimate goal is to generate preclinical data on L7Ae-mediated treatment for Orthomyxoviridae infections, aiming to advance it towards a clinical usage.