Procyanidin B3 and Its Derivatives Alleviate Neuronal Injury by Targeting G3BP1 for Ischemic Stroke Therapy

Ischemic stroke (IS) is a leading cause of mortality and disability worldwide, but effective therapeutic options are limited. In this study, a chemical proteomic strategy is employed using the active compound procyanidin B3 (PB3) as a chemical probe to identify the therapeutic targets for IS. It is discovered that the Ras GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a key target of PB3, which exerts a neuroprotective effect by inhibiting the degradation of stress granules and reducing apoptosis. Based on this finding, 14 PB3 derivatives are designed and synthesized, among which compound 6c exhibited potent neuroprotective activity and favorable blood-brain barrier permeability. This study not only establishes G3BP1 as a promising therapeutic target for IS but also highlights the potential of PB3 and its derivatives for the development of IS therapeutic agents.