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.
- Amyloid fibrillation
- Discrete molecular dynamics simulations
- High-throughput dynamic light scattering
- Human islet amyloid polypeptide
- Hydroxyl-terminated polyamidoamine dendrimer
- Protein aggregation
Gurzov, E., Wang, B., Pilkington, E. H., Chen, P., Kakinen, A., Stanley, W. J., Litwak, S. A., Hanssen, E. G., Davis, T. P.
, Ding, F., & Ke, P. C.
(2016). Inhibition of hIAPP amyloid aggregation and pancreatic β-cell toxicity by OH-terminated PAMAM dendrimer
(12), 1615-1626. https://doi.org/10.1002/smll.201502317