Targeted Protein Degrader from Ginkgo to Mitigate Amyloid β-Induced Neurotoxicity

Protein degradation through the autophagy-lysosome process by eukaryotic cells is a major pathway to remove unwanted proteins, organelles, and invading pathogens. It is also an emerging intervention strategy to selectively eliminate inaccessible toxic amyloid proteins to prevent amyloid β (Aβ)-induced neurotoxicity. Currently, there is no natural product-derived peptide that targets amyloid proteins for degradation through the autophagy-lysosome pathway. We recently discovered a new peptide family from <i>Ginkgo biloba</i> nuts, which we termed β-ginkgotides. The prototype β-gB1 is 20-residue in length, cross-braced by three disulfides, and stable to proteolytic degradation. Importantly, it has an LC3-interacting region (LIR) motif, which promotes selective autophagy to degrade harmful proteins and to prevent cell death. Here, we show that β-gB1 is cell-penetrating, primarily entering cells through energy-dependent endocytosis, and protects Aβ-induced neurotoxicity using an SH-SY5Y neuronal cell-based model. Functional studies using synthetic β-gB1 revealed that it impedes Aβ accumulation and reverses the altered gene expression associated with Alzheimer's disease (AD) pathophysiology induced by Aβ. Importantly, β-gB1 maintains cellular homeostasis and enhances the clearance of Aβ aggregates through selective autophagy, thereby safeguarding neurons from Aβ toxicity. Collectively, these results support that β-ginkgotide is a first-in-class cysteine-rich peptide (CRP)-based targeted protein degrader and underscore its potential as a novel and promising neuroprotective therapeutic to manage Aβ-induced neurotoxicity in AD and other neurodegenerative disorders.