A peptidomimetic approach to targeting pre-amyloidogenic states in type II diabetes.
Protein fiber formation is associated with diseases ranging from Alzheimer's to type II diabetes. For many systems, including islet amyloid polypeptide (IAPP) from type II diabetes, fibrillogenesis can be catalyzed by lipid bilayers. Paradoxically, amyloid fibers are beta sheet rich while membrane-stabilized states are alpha-helical. Here, a small molecule alpha helix mimetic, IS5, is shown to inhibit bilayer catalysis of fibrillogenesis and to rescue IAPP-induced toxicity in cell culture. Importantly, IAPP:IS5 interactions localize to the putative alpha-helical region of IAPP, revealing that alpha-helical states are on pathway to fiber formation. IAPP is not normally amyloidogenic as its cosecreted partner, insulin, prevents self-assembly. Here, we show that IS5 inhibition is synergistic with insulin. IS5 therefore represents a new approach to amyloid inhibition as the target is an assembly intermediate that may additionally restore functional IAPP expression.
Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114, USA.
James A
JA
Hebda
Ishu
I
Saraogi
Mazin
M
Magzoub
Andrew D
AD
Hamilton
Andrew D
AD
Miranker
D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology*; D000682:Amyloid / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004357:Drug Synergism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D058228:Islet Amyloid Polypeptide; D008051:Lipid Bilayers / Q000378:metabolism; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D051381:Rats; D016415:Sequence Alignment
D000085:Acetates; D000631:Aminopyridines; D000682:Amyloid; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D008051:Lipid Bilayers