Affiliation: | 1. CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh India
These authors contributed equally to this work.;2. CSIR-Indian Institute of Toxicology Research, Lucknow, 226 001, Uttar Pradesh India;3. CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201 002 India;4. CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh India;5. CompuNet, Istituto Italiano di Tecnologia (IIT), Via Morego 30, 16163 Genova, Italy |
Abstract: | 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. |