Small-Molecule Inhibitor Prevents Insulin Fibrillogenesis and Preserves Activity
- 29 April 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Molecular Pharmaceutics
- Vol. 17 (6), 1827-1834
- https://doi.org/10.1021/acs.molpharmaceut.9b01080
Abstract
Amyloidosis is a well-known, but poorly understood phenomenon caused by the aggregation of proteins, often leading to pathological conditions. For example, the aggregation of insulin poses significant challenges during the preparation of pharmaceutical insulin formulations commonly used to treat diabetic patients. Therefore, it is essential to develop inhibitors of insulin aggregation for potential biomedical applications, and for important mechanistic insights into amyloidogenic pathways. Here, we have identified a small molecule M1, which causes a dose dependent reduction in insulin fibril formation. Biophysical analyses and docking results suggest that M1 likely binds to partially unfolded insulin intermediates. Further, M1-treated insulin had lower cytotoxicity, and remained functionally active in regulating cell proliferation in cultured Drosophila wing epithelium. Thus, M1 is of great interest as a novel agent for inhibiting insulin aggregation during biopharmaceutical manufacturing.Keywords
Funding Information
- University Grants Commission
- Science and Engineering Research Board
- Department of Biotechnology , Ministry of Science and Technology
- Department of Science and Technology, Ministry of Science and Technology
- Indian Institute of Science Education and Research Bhopal
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