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 - Funding Information:
This research was supported, in part, by NIH GM094693 to A.D.M. and an American Diabetes Association mentor-based postdoctoral fellowship to D.E.S. We are thankful to the laboratories of Prof. Nilay Hazari and Prof. David A. Spiegel (Chemistry Department, Yale University) for providing instruments and space to perform carbonylation and microwave-based reactions en route to the synthesis of oligopyridylamides.
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
VL - 22
SP - 369
EP - 378
JO - Cell Chemical Biology
JF - Cell Chemical Biology
SN - 2451-9448
IS - 3
M1 - 3006
ER -