TY - JOUR
T1 - Inhibition of hIAPP amyloid aggregation and pancreatic β-cell toxicity by OH-terminated PAMAM dendrimer
AU - Gurzov, Esteban
AU - Wang, Bo
AU - Pilkington, Emily Helen
AU - Chen, Pengyu
AU - Kakinen, Aleksandr
AU - Stanley, William J
AU - Litwak, Sara Alejandra
AU - Hanssen, Eric G
AU - Davis, Thomas Paul
AU - Ding, Feng
AU - Ke, Pu Chun
PY - 2016/3/23
Y1 - 2016/3/23
N2 - 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.
AB - 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.
KW - Amyloid fibrillation
KW - Cytotoxicity
KW - Discrete molecular dynamics simulations
KW - High-throughput dynamic light scattering
KW - Human islet amyloid polypeptide
KW - Hydroxyl-terminated polyamidoamine dendrimer
KW - Protein aggregation
UR - http://www.scopus.com/inward/record.url?scp=84969405472&partnerID=8YFLogxK
U2 - 10.1002/smll.201502317
DO - 10.1002/smll.201502317
M3 - Article
VL - 12
SP - 1615
EP - 1626
JO - Small
JF - Small
SN - 1613-6810
IS - 12
ER -