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Inhibition of hIAPP Amyloid Aggregation and Pancreatic β-Cell Toxicity by OH-Terminated PAMAM Dendrimer.
- Source :
-
Small (Weinheim an der Bergstrasse, Germany) [Small] 2016 Mar 23; Vol. 12 (12), pp. 1615-26. Date of Electronic Publication: 2016 Jan 25. - Publication Year :
- 2016
-
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.<br /> (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Benzothiazoles
Cell Death drug effects
Cytoprotection drug effects
Humans
Hydroxylation
Insulin-Secreting Cells drug effects
Models, Molecular
Protein Multimerization drug effects
Thiazoles metabolism
Amyloid metabolism
Dendrimers toxicity
Insulin-Secreting Cells pathology
Islet Amyloid Polypeptide metabolism
Protein Aggregates drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1613-6829
- Volume :
- 12
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Small (Weinheim an der Bergstrasse, Germany)
- Publication Type :
- Academic Journal
- Accession number :
- 26808649
- Full Text :
- https://doi.org/10.1002/smll.201502317