TY - JOUR
T1 - Islet amyloid-induced cell death and bilayer integrity loss share a molecular origin targetable with oligopyridylamide-based α-helical mimetics
AU - Kumar, Sunil
AU - Schlamadinger, Diana E.
AU - Brown, Mark A.
AU - Dunn, Joanna M.
AU - Mercado, Brandon
AU - Hebda, James A.
AU - Saraogi, Ishu
AU - Rhoades, Elizabeth
AU - Hamilton, Andrew D.
AU - Miranker, Andrew D.
N1 - Publisher Copyright:
©2015 Elsevier Ltd All rights reserved
PY - 2015/3/19
Y1 - 2015/3/19
N2 - Summary Islet amyloid polypeptide (IAPP) is a hormone cosecreted with insulin. IAPP proceeds through a series of conformational changes from random coil to β-sheet via transient α-helical intermediates. An unknown subset of these events are associated with seemingly disparate gains of function, including catalysis of self-assembly, membrane penetration, loss of membrane integrity, mitochondrial localization, and finally, cytotoxicity, a central component of diabetic pathology. A series of small molecule, α-helical mimetics, oligopyridylamides, was previously shown to target the membrane-bound α-helical oligomeric intermediates of IAPP. In this study, we develop an improved, microwave-assisted synthesis of oligopyridylamides. A series of designed tripyridylamides demonstrate that lipid-catalyzed self-assembly of IAPP can be deliberately targeted. In addition, these molecules affect IAPP-induced leakage of synthetic liposomes and cellular toxicity in insulin-secreting cells. The tripyridylamides inhibit these processes with identical rank orders of effectiveness. This indicates a common molecular basis for the disparate set of observed effects of IAPP.
AB - Summary Islet amyloid polypeptide (IAPP) is a hormone cosecreted with insulin. IAPP proceeds through a series of conformational changes from random coil to β-sheet via transient α-helical intermediates. An unknown subset of these events are associated with seemingly disparate gains of function, including catalysis of self-assembly, membrane penetration, loss of membrane integrity, mitochondrial localization, and finally, cytotoxicity, a central component of diabetic pathology. A series of small molecule, α-helical mimetics, oligopyridylamides, was previously shown to target the membrane-bound α-helical oligomeric intermediates of IAPP. In this study, we develop an improved, microwave-assisted synthesis of oligopyridylamides. A series of designed tripyridylamides demonstrate that lipid-catalyzed self-assembly of IAPP can be deliberately targeted. In addition, these molecules affect IAPP-induced leakage of synthetic liposomes and cellular toxicity in insulin-secreting cells. The tripyridylamides inhibit these processes with identical rank orders of effectiveness. This indicates a common molecular basis for the disparate set of observed effects of IAPP.
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U2 - 10.1016/j.chembiol.2015.01.006
DO - 10.1016/j.chembiol.2015.01.006
M3 - Article
C2 - 25754474
AN - SCOPUS:84925538053
SN - 1074-5521
VL - 22
SP - 369
EP - 378
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 3
M1 - 3006
ER -