Islet amyloid-induced cell death and bilayer integrity loss share a molecular origin targetable with oligopyridylamide-based α-helical mimetics.

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.

Small molecule screening in context: lipid-catalyzed amyloid formation.

Islet Amyloid Polypeptide (IAPP) is a 37-residue hormone cosecreted with insulin by the β-cells of the pancreas. Amyloid fiber aggregation of IAPP has been correlated with the dysfunction and death of these cells in type II diabetics. The likely mechanisms by which IAPP gains toxic function include energy independent cell membrane penetration and induction of membrane depolarization.

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.

The interplay of catalysis and toxicity by amyloid intermediates on lipid bilayers: insights from type II diabetes.

The dynamics, energies, and structures governing protein folding are critical to biological function. Amyloidoses are a class of disease defined, in part, by the misfolding and aggregation of functional protein precursors into fibrillar states. Amyloid fibers contribute to the pathology of many diseases, including type II diabetes, Alzheimer's, and Parkinson's.

Amide inequivalence in the fibrillar assembly of islet amyloid polypeptide.

Amyloid fibers are aggregated, yet highly ordered, beta-sheet-rich assemblies of misfolded proteins. Order is established in such systems following profiles indicative of nucleation-dependent assembly. Nucleation dependence suggests that specific interactions, such as long-range contacts and/or strand registration, are critical to establishing initial fiber structure.

Conserved and cooperative assembly of membrane-bound alpha-helical states of islet amyloid polypeptide.

The conversion of soluble protein into beta-sheet-rich amyloid fibers is the hallmark of a number of serious diseases. Precursors for many of these systems (e.g.