Exploration of Isoquinoline Alkaloids as Potential Inhibitors against Human Islet Amyloid Polypeptide

Abstract

Type-2 diabetes mellitus (T2DM) is one of the most concerning public health problems because of its high incidence, multiple complications, and difficult treatment. Human islet amyloid polypeptide (hIAPP) is closely linked to T2DM because its abnormal self-assembly causes membrane damage and cell dysfunction. The development of potential inhibitors to prevent hIAPP fibrillation is a promising strategy for the intervention and treatment of diabetes. Natural isoquinoline alkaloids are used as effective medication that targets different biomolecules. Although studies explored the efficacy of berberine, jatrorrhizine, and chelerythrine in diabetes, the underlying mechanism remains unclear. Herein, three isoquinoline alkaloids are selected to reveal their roles in hIAPP aggregation, disaggregation, and cell protection. All three compounds displayed good inhibitory effects on peptide fibrillation, scattered the preformed fibrils into small oligomers and most monomers, and upregulated cell viability by reducing hIAPP oligomerization. Moreover, combined biophysical analyses indicated that the compounds affected the β-sheet structure and hydrophobicity of polypeptides significantly, and the benzo­[c]­phenanthridine structure of chelerythrine was beneficial to the inhibition of hIAPP aggregation and their hydrophobic interaction, compared with that of berberine and jatrorrhizine. Our work elaborated the effects of these alkaloids on hIAPP fibrillation and reveals a possible mechanism for these compounds against T2DM.

Chiral 8-Amino-5,6,7,8-tetrahydroquinoline Derivatives in Metal Catalysts for the Asymmetric Transfer Hydrogenation of 1-Aryl Substituted-3,4-dihydroisoquinolines as Alkaloids Precursors

“…[ 15 , 16 , 17 , 18 , 19 ] thus evoking the need for new catalysts able to broaden the scope toward the most challenging dihydroisoquinolines (DHIQs). The related reduction products, namely tetrahydroisoquinolines (THIQs), indeed account for an important class of alkaloids and semi-synthetic derivatives endowed with multiple relevant biological properties ( Figure 1 ) [ 20 , 21 , 22 , 23 , 24 ].…”

Illustrating the Effect of Small Molecules Derived from Natural Resources on Amyloid Peptides

“…Other isoquinolines are also able to inhibit Aβ aggregation and disaggregate preformed Aβ 40 aggregates in the order chelerythrine > berberine > palmatine. The benzo­[ c ]­phenanthridine structure of chelerythrine adds to its higher efficiency in preventing hIAPP oligomerization, compared to berberine and jatrorrhizine . Nitidine and avicine, two isoquinoline alkaloids from the roots of Zanthoxylum rigidum , are potent candidates targeting dual cholinesterase inhibition as well as Aβ aggregation .…”

Gold Nanoclusters Enhance the Efficacy of the Polymer-Based Chaperone in Restoring and Maintaining the Native Conformation of Human Islet Amyloid Polypeptide

“…Thus, inhibiting the generation of toxic oligomers and eliminating them have been acknowledged as promising therapies for T2D and other protein conformational diseases, which are intensely concerned by researchers. This strategy has been fulfilled by small molecules, peptides, , antibodies, metal-ion chelators, , and nanoparticles, , capable of inhibiting the aggregation and fibrillation of hIAPP and other amyloid protein in vitro , by hydrophobic interactions, electrostatic interactions, hydrogen bonding, and aromatic π–π stacking. − However, there is no effective medicine developed for T2D or other protein conformational diseases till now . A key scientific problem lies that how to restore and maintain the native conformation of hIAPP and other proteins, rather than just inhibit their aggregation and fibrillation.…”