Benzbromarone, Quercetin, and Folic Acid Inhibit Amylin Aggregation

Abstract

Human Amylin, or islet amyloid polypeptide (hIAPP), is a small hormone secreted by pancreatic β-cells that forms aggregates under insulin deficiency metabolic conditions, and it constitutes a pathological hallmark of type II diabetes mellitus. In type II diabetes patients, amylin is abnormally increased, self-assembled into amyloid aggregates, and ultimately contributes to the apoptotic death of β-cells by mechanisms that are not completely understood. We have screened a library of approved drugs in order to identify inhibitors of amylin aggregation that could be used as tools to investigate the role of amylin aggregation in type II diabetes or as therapeutics in order to reduce β-cell damage. Interestingly, three of the compounds analyzed—benzbromarone, quercetin, and folic acid—are able to slow down amylin fiber formation according to Thioflavin T binding, turbidimetry, and Transmission Electron Microscopy assays. In addition to the in vitro assays, we have tested the effect of these compounds in an amyloid toxicity cell culture model and we have found that one of them, quercetin, has the ability to partly protect cultured pancreatic insulinoma cells from the cytotoxic effect of amylin. Our data suggests that quercetin can contribute to reduce oxidative damage in pancreatic insulinoma β cells by modulating the aggregation propensity of amylin.

Influence of the Aqueous Environment on Protein Structure—A Plausible Hypothesis Concerning the Mechanism of Amyloidogenesis

“…The topic of amyloidogenesis has been the subject of many scientific endeavors and a great variety of papers have been published, approaching the problem from all possible angles: diagnostics [63][64][65][66], therapeutic [67][68][69][70][71][72][73][74][75][76][77][78][79][80][81] and structural/molecular [82][83][84][85]. Our publication does not, however, discuss amyloidogenesis as such, but rather the molecular processes which lead to the formation of fibrillary aggregates commonly referred to as amyloids.…”

Unfolding Novel Mechanisms of Polyphenol Flavonoids for Better Glycaemic Control: Targeting Pancreatic Islet Amyloid Polypeptide (IAPP)

“…Rutin is thought to be the main glycosidic form of quercetin in the diet [ 82 ] and is found abundantly in buckwheat [ 83 , 84 ] ( Table 1 ). Additionally, quercetin has been shown to have a greater antioxidant activity compared to polyphenolic acids without this structure, due to 3-hydroxy groups and conjugated π bonds [ 73 ] ( Figure 2 ); hence the purported beneficial effects of quercetin and quercetin- O -rutinoside (rutin) in the improvement of glycaemic indices in recent in vitro [ 85 ] and animal models [ 86 , 87 , 88 , 89 , 90 ] studies, as well as in preventing amylin misfolding and aggregation [ 91 , 92 , 93 , 94 ].…”

“…In vivo studies support the use of quercetin [ 94 ] and rutin [ 93 ] as antioxidants that additionally modulate IAPP aggregation, the latter using transgenic mice engineered to develop features of T2D in humans. This is in line with other studies that have shown that rutin interacts with soluble hA oligomers to prevent the formation of cytotoxic aggregates and to protect against Fas-mediated destruction of islet cells [ 8 , 91 ].…”

Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer

“…Interest in this drug was found in other recent research studies. BBM was reported to be an effective inhibitor of amylin aggregation [ 37 ]. BBM was shown to inhibit retinol-dependent RBP4-TTR interaction for treatment of age-related macular degeneration [ 38 ].…”