Title: Inhibition of hIAPP Amyloid Aggregation and Pancreatic beta-Cell Toxicity by OH-Terminated PAMAM Dendrimer
Authors: Gurzov, EN
Wang, B
Pilkington, EH
Chen, PY
Kakinen, A
Stanley, WJ
Litwak, SA
Hanssen, EG
Davis, TP
Ding, F
Ke, PC
Issue Year: 2016
Series Small:
Abstract Human islet amyloid polypeptide (hIAPP, or amylin) forms amyloid deposits in the islets of Langerhans, a phenomenon that is associated with type-2 diabetes impacting millions of people worldwide. Accordingly, strategies against hIAPP aggregation are essential for the prevention and eventual treatment of the disease. Here, it is shown that generation-3 OH-terminated poly(amidoamine) dendrimer, a polymeric nanoparticle, can effectively halt the aggregation of hIAPP and shut down hIAPP toxicity in pancreatic MIN6 and NIT-1 cells as well as in mouse islets. This finding is supported by high-throughput dynamic light scattering experiment and thioflavin T assay, where the rapid evolution of hIAPP nucleation and elongation processes is halted by the addition of the dendrimer up to 8 h. Discrete molecular dynamics simulations further reveal that hIAPP residues bound strongly with the dendrimer near the c-terminal portion of the peptide, where the amyloidogenic sequence (residues 22-29) locates. Furthermore, simulations of hIAPP dimerization reveal that binding with the dendrimer significantly reduces formation of interpeptide contacts and hydrogen bonds, thereby prohibiting peptide self-association and amyloidosis. This study points to a promising nanomedicinal strategy for combating type-2 diabetes and may have broader implications for targeting neurological disorders whose distinct hallmark is also amyloid fibrillation.
URI: https://publications.svi.edu.au/publications/6742
Other Identifiers 10.1002/smll.201502317
Publication type Article