Journal
ACS BIO & MED CHEM AU
Volume 2, Issue 3, Pages 205-221Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsbiomedchemau.1c00054
Keywords
aggregation; insulin; amyloid; inhibitors; insulin analogs
Funding
- SERB
- IISER Bhopal
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Protein aggregation leading to amyloid fibril formation has significant negative impacts on human health. In the case of insulin, its aggregation hinders proper glucose level control in diabetic patients. Therefore, understanding the mechanism of insulin fibrillation and developing inhibitors are crucial for diabetic therapies and enhancing our knowledge of protein amyloidosis.
Protein aggregation leading to the formation of amyloid fibrils has various adverse effects on human health ranging from fatigue and numbness to organ failure and death in extreme cases. Insulin, a peptide hormone commonly used to treat diabetes, undergoes aggregation at the site of repeated injections in diabetic patients as well as during its industrial production and transport. The reduced bioavailability of insulin due to aggregation hinders the proper control of glucose levels in diabetic patients. Thus, it is necessary to develop rational approaches for inhibiting insulin aggregation, which in turn requires a detailed understanding of the mechanism of fibrillation. Given the relative simplicity of insulin and ease of access, insulin has also served as a model system for studying amyloids. Approaches to inhibit insulin aggregation have included the use of natural molecules, synthetic peptides or small molecules, and bacterial chaperone machinery. This review focuses on insulin aggregation with an emphasis on its mechanism, the structural features of insulin fibrils, and the reported inhibitors that act at different stages in the aggregation pathway. We discuss molecules that can serve as leads for improved inhibitors for use in commercial insulin formulations. We also discuss the aggregation propensity of fast- and slow-acting insulin biosimilars, commonly administered to diabetic patients. The development of better insulin aggregation inhibitors and insights into their mechanism of action will not only aid diabetic therapies, but also enhance our knowledge of protein amyloidosis.
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