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

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).