Identification of Natural Products as Potential Pharmacological Chaperones for Protein Misfolding Diseases

Defective protein folding and accumulation of misfolded proteins is associated with neurodegenerative, cardiovascular, secretory, and metabolic disorders. Efforts are being made to identify small‐molecule modulators or structural‐correctors for conformationally destabilized proteins implicated in various protein aggregation diseases. Using a metastable‐reporter‐based primary screen, we evaluated pharmacological chaperone activity of a diverse class of natural products. We found that a flavonoid glycoside (C‐10, chrysoeriol‐7‐O‐β‐D‐glucopyranoside) stabilizes metastable proteins, prevents its aggregation, and remodels the oligomers into protease‐sensitive species. Data was corroborated with additional secondary screen with disease‐specific pathogenic protein. In vitro and cell‐based experiments showed that C‐10 inhibits α‐synuclein aggregation which is implicated in synucleinopathies‐related neurodegeneration. C‐10 interferes in its structural transition into β‐sheeted fibrils and mitigates α‐synuclein aggregation‐associated cytotoxic effects. Computational modeling suggests that C‐10 binds to unique sites in α‐synuclein which may interfere in its aggregation amplification. These findings open an avenue for comprehensive SAR development for flavonoid glycosides as pharmacological chaperones for metastable and aggregation‐prone proteins implicated in protein conformational diseases. The diversity of natural products was explored to identify small‐molecule based modulators or structural‐correctors for conformationally destabilized proteins implicated in various protein aggregation diseases. Through metastable‐reporter based primary screen and a secondary screen with disease‐specific pathogenic protein, pharmacological chaperone activity of flavonoid glycoside (C‐10, chrysoeriol‐7‐O‐β‐D‐glucopyranoside) is demonstrated. Data suggests that C‐10 stabilizes metastable protein, remodels the oligomers, inhibits protein aggregation and mitigates aggregation‐associated cytotoxic effects.