Inhibition of hIAPP Amyloid Aggregation and Pancreatic β‐Cell Toxicity by OH‐Terminated PAMAM Dendrimer |
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| Authors: | Esteban N. Gurzov Bo Wang Emily H. Pilkington Pengyu Chen Aleksandr Kakinen William J. Stanley Sara A. Litwak Eric G. Hanssen Thomas P. Davis Feng Ding Pu Chun Ke |
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| Affiliation: | 1. St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia;2. Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, Australia;3. Department of Physics and Astronomy, Clemson University, Clemson, SC, USA;4. ARC Centre of Excellence in Convergent Bio‐Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia;5. Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, USA;6. Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, VIC, Australia;7. Department of Chemistry, University of Warwick, Gibbet Hill, Coventry, UK |
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| 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. |
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| Keywords: | amyloid fibrillation cytotoxicity discrete molecular dynamics simulations human islet amyloid polypeptide high‐throughput dynamic light scattering hydroxyl‐terminated polyamidoamine dendrimer protein aggregation |
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