Small molecule interference of bilayer catalyzed fiber formation

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DESCRIPTION (provided by applicant): Islet amyloid polypeptide (IAPP) is a 37 residue peptide hormone cosecreted with insulin by the beta-cells of the pancreas. In patients with type II diabetes, IAPP aggregates as amyloid fiber in a process that is associated with ?-cell dysfunction and the subsequent loss of ? -cell mass. This is a process wholly analogous to cytotoxicity evident in other protein misfolding diseases, e.g. A? peptide from Alzheimer's disease. In general, the association of amyloid with cell death is supported by the observation that soluble oligomeric states of amyloid precursors induce disease-like toxicity when added to cultured cells or injected into model animals. These same states are observed associated with cellular membranes and can permeablize lipid bilayers in vitro. This correlation has led to the paradigm that membrane disruption by oligomeric states, either through pore formation, carpet or detergent-like effects, is a general mechanism of cytotoxicity among amyloid diseases. Our recent investigations in vitro have revealed that IAPP can bind lipid bilayers at concentrations well below that found in the secretory granule. This binding results in catalysis of its conversion into the ? -sheet rich amyloid state. Intriguingly, IAPP is initially stabilized into an ?-helical conformation upon membrane binding. This state then self-associates into a membrane bound, ? -helical oligomer. It is the latter that is correlated both with catalysis of amyloid formation, and with membrane disruption. The overall aim of this proposal is to screen for small molecules that alter the reaction profile of lipid bilayer catalyzed fiber formation. In this way, compounds will be found that affect fiber formation by targeting one of more of a discrete set of defined molecular interfaces. These categorizations will be then assessed with respect to their capacity to mediate membrane destabilization and IAPP mediated cell death. In patients with type II diabetes, the cells which make insulin eventually fail. Another hormone called islet amyloid polypeptide (IAPP) is made by the same cells, but can form structures which are toxic to the insulin secreting cells. The aim of this work is to find drug-sized molecules which prevent IAPP from forming these toxic structures.