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 β‐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. Towards diabetes therapeutic agents: Cucurbit[7]uril (CB[7])‐mediated supramolecular modulation of islet amyloid polypeptide aggregation is demonstrated. CB[7] efficiently interacts with different amino acid residues at the N terminus “hot segments” and alters IAPP aggregation. This type of macrocycle‐based approach has the potential for the development of type 2 diabetes therapeutic agents.