Peptides targeting RAB11A-FIP2 complex inhibit HPIV3, RSV, and IAV replication as broad-spectrum antivirals.

Background: The cytoskeletal framework plays a critical role in the early stages of human parainfluenza virus type 3 (HPIV3) replication, including viral mRNA synthesis and translation. However, its contribution to later stages of infection, particularly in the context of RNA biology, is not well understood. This study focuses on the role of the cytoskeleton in viral nucleocapsid (vRNP, a ribonucleoprotein complex essential for RNA virus replication) transport, assembly, and budding, and explores the cooperative role of the small GTPase RAB11A and its effector RAB11 family interacting protein 2 (FIP2) in vRNP trafficking. These processes are crucial for respiratory RNA viruses like respiratory syncytial virus (RSV) and influenza A virus (IAV), highlighting the importance of RNA-protein interactions in viral pathogenesis.

Results: Through the use of cytoskeleton-depolymerizing agents, the study identified actin microfilaments as indispensable for vRNP transport, viral assembly, and viral particle budding. It also revealed the importance of the RAB11A-FIP2 complex in these processes, which are critical for the intracellular trafficking of viral RNA. The development of peptides targeting the RAB11A-FIP2 complex led to the suppression of RAB11A function in infected cells, resulting in vRNP aggregation in the cytoplasm and reduced viral replication. The peptide YT-DRI showed strong broad-spectrum antiviral activity against HPIV3, RSV, and IAV in cellular and animal models and was effective against co-infections in vitro. The antiviral effects of YT-DRI were abolished upon deletion of RAB11A or core components of the RAB11A pathway.

Conclusion: This work introduces a promising broad-spectrum antiviral strategy for respiratory tract infections by targeting the RAB11A-FIP2 complex, which regulates the transport and assembly of viral RNA. By disrupting this pathway, YT-DRI effectively inhibits the replication of multiple respiratory RNA viruses, including HPIV3, RSV, and IAV.