期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
卷 218, 期 -, 页码 981-991出版社
ELSEVIER
DOI: 10.1016/j.ijbiomac.2022.07.155
关键词
Chemical chaperone; Excipient; Sulfonate; Inhibitors; Disaggregation
资金
- IISER Bhopal
- SERB
- Department of Biotechnology, Govt. of India [BT/PR29978/MED/30/2037/2018]
- UGC
This article introduces a novel amphiphilic molecule called PAD-S, which acts as a chemical chaperone to completely inhibit the fibrillation of insulin and its biosimilars. PAD-S can bind to the key hydrophobic regions of insulin, preventing its self-assembly and protecting cells from insulin amyloid-induced cytotoxicity.
The aggregation of proteins into ordered fibrillar structures called amyloids, and their disintegration represent major unsolved problems that limit the therapeutic applications of several proteins. For example, insulin, commonly used for the treatment of diabetes, is susceptible to amyloid formation upon exposure to non -physiological conditions, resulting in a loss of its biological activity. Here, we report a novel amphiphilic molecule called PAD-S, which acts as a chemical chaperone and completely inhibits fibrillation of insulin and its biosimilars. Mechanistic investigations and molecular docking lead to the conclusion that PAD-S binds to key hydrophobic regions of native insulin, thereby preventing its self-assembly. PAD-S treated insulin was biologi-cally active as indicated by its ability to phosphorylate Akt, a protein in the insulin signalling pathway. PAD-S is non-toxic and protects cells from insulin amyloid induced cytotoxicity. The high aqueous solubility and easy synthetic accessibility of PAD-S facilitates its potential use in commercial insulin formulations. Notably, PAD-S successfully disintegrated preformed insulin fibrils to non-toxic smaller fragments. Since the structural and mechanistic features of amyloids are common to several human pathologies, the understanding of the amyloid disaggregation activity of PAD-S will inform the development of small molecule disaggregators for other amyloids.
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