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bioRxiv · 10.64898/2026.09.18.752587

Model-Guided Engineering of NS1-Truncated Influenza OP7 Particles with Enhanced Interferon-Mediated Antiviral Activity

Piasecka, J.·Ruediger, D.·Reichl, U.·Kupke, S. Y.
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Abstract

Defective interfering particles (DIPs) represent promising antivirals against influenza A virus (IAV), yet strategies to further enhance their antiviral activity remain largely unexplored. Here, we engineered a next-generation OP7 DIP by truncating the viral interferon (IFN) antagonist non-structural protein 1 (NS1) to enhance IFN-mediated antiviral activity. A previously validated mathematical multiscale model predicted that loss of NS1 function would enhance antiviral activity, providing a mechanistic rationale for this design. We engineered OP7-trNS1 DIP, established a cell culture-based production process yielding infectious virus-free material, and evaluated its antiviral activity in human lung epithelial cells in vitro. OP7-trNS1 inhibited IAV replication by approx. two orders of magnitude more effectively than the parental OP7 DIP while inducing a stronger IFN response, consistent with the model predictions. Together, these findings demonstrate that reducing viral IFN antagonism is a viable strategy for rationally enhancing DIP antiviral activity and establish OP7-trNS1 as a promising candidate for further preclinical development.

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Piasecka, J., Ruediger, D., Reichl, U., Kupke, S. Y.. 2026-09-22. Model-Guided Engineering of NS1-Truncated Influenza OP7 Particles with Enhanced Interferon-Mediated Antiviral Activity. https://doi.org/10.64898/2026.09.18.752587

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