Targeting liquid organelles to develop new antiviral strategies against influenza A virus infections

Rising antiviral resistance, vaccine hesitancy, and more frequent zoonotic spillovers, amplified by climate change and ecosystem disruption, demand for more and different antiviral solutions. Most licensed influenza antivirals act by inhibiting viral protein functions and can be undermined by resistance. LOFlu_TREAT develops an evolution-resilient approach against epidemic and pandemic influenza A virus (IAV) by modulating the material properties of virus-induced biomolecular condensates, membraneless compartments that support key steps of replication. IAV is an important human pathogen from the Orthomyxoviridea family. When it infects a cell, it forms specialised condensates, viral inclusions, that coordinate assembly of its segmented genome of eight distinct viral ribonucleoproteins (vRNPs). In ERC CoG LOFlu, we showed that hardening these inclusions blocks infection in vitro and in vivo, with selectivity and no detectable toxicity; yet the only available hardening molecule, the molecular glue called nucleozin, rapidly selected resistant IAV escape mutants. LOFlu_TREAT addresses the need for more and different antivirals by engineering vRNP-clips, a different scalable class of molecular glues. It also addresses the need to mitigate antiviral resistance emergence by advancing a defined multi-vRNP-clip formulation that raises the barrier to resistance while remaining selectively active in infected cells with an expected reduced toxicity profile, and broadly effective against other members of the Orthomyxoviridae family. As a long-term vision, this condensate-targeting platform could extend to other viral families dependent on condensates, including Pneumoviridae, Rhabdoviridae, Filoviridae, Retroviridae, Paramyxoviridae, and Reoviridae. By integrating biophysical modulation, experimental evolution, and AI-enabled design, LOFlu_TREAT aims to open a new antiviral modality, accelerate drug innovation, and strengthen Europe's capacity for infectious disease preparedness and intervention.