Islet Amyloid-Induced Cell Death and Bilayer Integrity Loss Share a Molecular Origin Targetable with Oligopyridylamide-Based α-Helical Mimetics

• Published in: Chemistry & biology Vol. 22; no. 3; pp. 369 - 378
• Main Authors: Kumar, Sunil, Schlamadinger, Diana E., Brown, Mark A., Dunn, Joanna M., Mercado, Brandon, Hebda, James A., Saraogi, Ishu, Rhoades, Elizabeth, Hamilton, Andrew D., Miranker, Andrew D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 19.03.2015
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Amino Acid Sequence; Animals; Apoptosis - physiology; Biomimetic Materials - chemical synthesis; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Cell Line, Tumor; Drug Design; Humans; Insulinoma; Islet Amyloid Polypeptide - chemistry; Islet Amyloid Polypeptide - metabolism; Lipid Bilayers - chemistry; Lipid Bilayers - metabolism; Liposomes - chemistry; Liposomes - metabolism; Membrane Fluidity - physiology; Microwaves; Models, Molecular; Molecular Sequence Data; Pancreatic Neoplasms; Protein Structure, Secondary; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Rats; Structure-Activity Relationship
• ISSN: 1074-5521; 1879-1301
• DOI: 10.1016/j.chembiol.2015.01.006

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. [Display omitted] •A series of derivitizable oligopyridylamides is designed and synthesized•Oligopyridylamides target α-helical structures of islet amyloid polypeptide (IAPP)•Membrane-bound α-helical oligomers of IAPP are associated with diabetes pathology•The study suggests a common precursor underpins several IAPP functions A library of oligopyridylamide-based helical mimetics was designed and synthesized to target membrane-associated α-helical intermediates of islet amyloid polypeptide, a protein implicated in type 2 diabetes. Oligopyridylamides slow the rate of IAPP amyloid assembly and reduce membrane poration and toxicity in a rank order that links these functions.