期刊
BIOCHEMISTRY
卷 59, 期 15, 页码 1482-1492出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.0c00076
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资金
- Ministry of Science and Technology, Taiwan [MOST105-2113-M-03-0010-MY2, MOST105-2113-M-003-014-MY2, MOST1062320-B-006-058-MY3]
- Department of Chemistry, Fu Jen Catholic University
- Department of Chemistry, National Taiwan Normal University
- Department of Pharmacology, College of Medicine, National Cheng Kung University
Aggregation of polypeptides and proteins is commonly associated with human and other vertebrate diseases. For example, amyloid plaques consisting of amyloid-beta proteins are frequently identified in Alzheimers disease and islet amyloid formed by islet amyloid polypeptide (IAPP, amylin) can be found in most patients with type 2 diabetes (T2D). Although many fluorescent dyes have been developed to stain amyloid fibrils, very few examples have been designed for IAPP. In this study, a series of environmentally sensitive fluorescent probes using flavonoid as a scaffold design are rationally designed and synthesized. One of these probes, namely 3-HF-ene-4'-OMe, can bind to IAPP fibrils but not nonfibrillar IAPP by exhibiting a much stronger fluorescent enhancement at 535 nm. In addition, this probe shows better detection sensitivity to IAPP fibrils compared with that of conventionally used thioflavin-T. We demonstrate that 3-HF-ene-4'-OMe can be used to monitor the kinetics of IAPP fibril formation in vitro even in the presence an amyloid inhibitor. To test the specificity of the probe, we attempt to incubate this probe with amyloid fibrils formed from other amyloidogenic proteins. Interestingly, this probe shows different responses when mixed with these fibrils, suggesting the mode of binding of this probe on these fibrils could be different. Moreover, we show that this probe is not toxic to pancreatic mouse beta-cells. Further structural optimization based on the structure of 3-HF-ene-4'-OMe may yield a specific probe for imaging islet amyloid in the pancreas. That would improve our understanding of the relationship between islet amyloid and T2D.
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