The primary goal of this proposal is the design of small molecule compounds which target newly identified protein structures with direct relevance to insulin secreting 2-cell viability in type II diabetes. Islet amyloid polypeptide (IAPP) is a 37-residue peptide hormone, which is co-secreted with insulin by the 2-cells of the endocrine pancreas. IAPP belongs to a class of aggregation prone proteins, which includes A2 from Alzheimer's, in which a wild-type protein precursor irreversibly forms/folds into 2-sheet rich fibrillar amyloid plaques. The origin of 2-cell death in type II diabetes is poorly understood. Like most amyloid diseases, it is the presence, rather than the extent, of amyloid deposition that is correlated with pathology. Instead, it is the intermediates of the assembly reaction that have been implicated in cell death. Importantly, this cytotoxicity is mediated by the formation of membrane bound protein structures. In the case of IAPP, this is highly intriguing since, despite the 2-sheet nature of mature amyloid, membrane bound states are 1-helical. The overall hypothesis pursued by this proposal is that small-molecule, structure based targeting of pre-amyloidogenic states will enable elucidation of the mechanism of IAPP induced cytotoxicity. These efforts will provide novel descriptions of IAPP oligomerization at a molecular level, and provide a rational design path for the creation of lead compounds that ameliorate 2-cell death. Our concurrently pursued aims include synergistic efforts in synthetic chemistry, cell and structural biology. Importantly, we will target the 1-helical intermediates of IAPP by synthesizing small molecules designed to mimic the surface presentation of one edge of an 1-helix. Cellular methods will be developed to assess toxicity and localization of IAPP. Diffraction, NMR and computational methods will be employed to elucidate the alternative oligomeric states at atomic resolution and to provide structure based guidance for small molecule synthesis.

Public Health Relevance

Changes to the shape of a protein surface can result in its inadvertent assembly into toxic structures. This process occurs in numerous diseases including type II diabetes and Alzheimer's. A novel synthetic chemistry approach is proposed that allows for the mimicking of protein surface using small molecules. This will enable the testing of hypotheses about the molecular basis of toxicity in the insulin secreting cells of type II diabetics.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Macromolecular Structure and Function D Study Section (MSFD)
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Fabian, Miles
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Yale University
Schools of Medicine
New Haven
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Kumar, Sunil; Birol, Melissa; Miranker, Andrew D (2016) Foldamer scaffolds suggest distinct structures are associated with alternative gains-of-function in a preamyloid toxin. Chem Commun (Camb) 52:6391-4
Kumar, Sunil; Birol, Melissa; Schlamadinger, Diana E et al. (2016) Foldamer-mediated manipulation of a pre-amyloid toxin. Nat Commun 7:11412
Kumar, Sunil; Schlamadinger, Diana E; Brown, Mark A et al. (2015) Islet amyloid-induced cell death and bilayer integrity loss share a molecular origin targetable with oligopyridylamide-based ?-helical mimetics. Chem Biol 22:369-78
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Nath, Abhinav; Schlamadinger, Diana E; Rhoades, Elizabeth et al. (2015) Structure-Based Small Molecule Modulation of a Pre-Amyloid State: Pharmacological Enhancement of IAPP Membrane-Binding and Toxicity. Biochemistry 54:3555-64
Schlamadinger, Diana E; Miranker, Andrew D (2014) Fiber-dependent and -independent toxicity of islet amyloid polypeptide. Biophys J 107:2559-66
Hebda, James A; Magzoub, Mazin; Miranker, Andrew D (2014) Small molecule screening in context: lipid-catalyzed amyloid formation. Protein Sci 23:1341-8
Kumar, Sunil; Brown, Mark A; Nath, Abhinav et al. (2014) Folded small molecule manipulation of islet amyloid polypeptide. Chem Biol 21:775-81
Last, Nicholas B; Miranker, Andrew D (2013) Common mechanism unites membrane poration by amyloid and antimicrobial peptides. Proc Natl Acad Sci U S A 110:6382-7
Last, Nicholas B; Schlamadinger, Diana E; Miranker, Andrew D (2013) A common landscape for membrane-active peptides. Protein Sci 22:870-82

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