title: Inhibition of hIAPP Amyloid Aggregation and Pancreatic β-Cell Toxicity by OH-Terminated PAMAM Dendrimer.
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.
authors.affiliation: St Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, VIC, 3065, Australia.|Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, Australia.
authors.forename: Esteban N
authors.initials: EN
authors.lastname: Gurzov
authors.affiliation: Department of Physics and Astronomy, Clemson University, Clemson, SC, 29634, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
authors.forename: Emily H
authors.initials: EH
authors.lastname: Pilkington
authors.affiliation: Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, 28109, USA.
authors.forename: Pengyu
authors.initials: P
authors.lastname: Chen
authors.affiliation: ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Kakinen
authors.affiliation: St Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, VIC, 3065, Australia.|Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, Australia.
authors.forename: William J
authors.initials: WJ
authors.lastname: Stanley
authors.affiliation: St Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, VIC, 3065, Australia.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Litwak
authors.affiliation: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, VIC, 3010, Australia.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Hanssen
authors.affiliation: ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.|Department of Chemistry, University of Warwick, Gibbet Hill, Coventry, CV4 7AL, UK.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Davis
authors.affiliation: Department of Physics and Astronomy, Clemson University, Clemson, SC, 29634, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
authors.affiliation: ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
authors.forename: Pu Chun
authors.initials: PC
authors.lastname: Ke
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D052160:Benzothiazoles; D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D050091:Dendrimers / Q000633:toxicity*; D006801:Humans; D006900:Hydroxylation; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology*; D058228:Islet Amyloid Polypeptide / Q000378:metabolism*; D008958:Models, Molecular; D066329:Protein Aggregates / Q000187:drug effects*; D055503:Protein Multimerization / Q000187:drug effects; D013844:Thiazoles / Q000378:metabolism
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D050091:Dendrimers; D058228:Islet Amyloid Polypeptide; C104700:PAMAM Starburst; D066329:Protein Aggregates; D013844:Thiazoles; C009462:thioflavin T
keywords: amyloid fibrillation; cytotoxicity; discrete molecular dynamics simulations; high-throughput dynamic light scattering; human islet amyloid polypeptide; hydroxyl-terminated polyamidoamine dendrimer; protein aggregation