Cucurbit[7]uril Inhibits Islet Amyloid Polypeptide Aggregation by Targeting N Terminus Hot Segments and Attenuates Cytotoxicity

Two hot segments within an islet amyloid polypeptide are responsible for its self-assembly, which in turn is linked to the decline of beta-cells in type 2 diabetes (T2D). A readily available water-soluble, macrocyclic host, cucurbit[7]uril (CB[7]), effectively inhibits islet amyloid polypeptide (IAPP) aggregation through ion-dipole and hydrophobic interactions with different residues of the monomeric peptide in its random-coil conformation. A HSQC NMR study shows that CB[7] likely modulates IAPP self-assembly by interacting with and masking major residues present in the hot segments at the N terminus. CB[7] also prevents the formation of toxic oligomers and inhibits seed-catalyzed fibril proliferation. Importantly, CB[7] recovers rat insulinoma cells (RIN-m) from IAPP-assembly associated cytotoxicity.

Automated summary

This study demonstrates that cucurbit[7]uril (CB[7]) can effectively inhibit the aggregation of islet amyloid polypeptide (IAPP) by interacting with the hot segments of IAPP and preventing the formation of toxic oligomers. CB[7] also protects rat insulinoma cells from cytotoxicity associated with IAPP assembly.