Dual-target GSPT1 and IKZF1/3 degrader: A broad-spectrum antiviral strategy validated in a natural host

As viral pandemics continue to evolve, the limitations of conventional direct-acting antivirals like remdesivir and oseltamivir have become a global challenge—specifically their vulnerability to mutational resistance and their inability to suppress life-threatening cytokine storms. Our study introduces AB138, a first-in-class bifunctional molecular glue degrader that redefines the antiviral landscape by co-targeting two pivotal host factors: GSPT1 (the protein translation gatekeeper) and IKZF1/3 (key immune regulators). This work represents a series of transformative breakthroughs:1.     Elucidating a novel antiviral mechanism: we report the first demonstration IKZF1/3 degradation possesses direct antiviral activity and mitigates immunopathology via immune regulation in a natural host model. This work provides the foundational rationale for developing IKZF1/3-co-targeting dual degraders.2.     Innovative "Double-Strike" Mechanism: By achieving synergistic degradation of GSPT1 and IKZF1/3, AB138 simultaneously arrests viral protein synthesis across multiple families (Coronaviridae and Orthomyxoviridae) and restores immune homeostasis to prevent immunopathology.3.     Superior Natural Host Model: For the first time, we conducted the therapeutic validation of an antiviral degrader in a natural host (canine/canine respiratory coronavirus). This approach transcends the limitations of conventional rodent models and markedly elevates the clinical translational value of the study.4.     Pivotal Translational Milestone: Most significantly, this is the first study to concurrently demonstrate both the in vivo safety and robust therapeutic efficacy of a GSPT1 degrader within the same large animal model. These high-quality preclinical data address a long-standing translational gap, providing core evidentiary support for the clinical advancement of GSPT1-targeting therapeutics beyond oncology.