Small molecule screening in context

Lipid-catalyzed amyloid formation

James A. Hebda, Mazin Magzoub, Andrew D. Miranker

    Research output: Contribution to journalArticle

    Abstract

    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. These processes have been correlated with solution biophysical observations of lipid bilayer catalyzed acceleration of amyloid formation. Although the relationship between amyloid formation and toxicity is poorly understood, the fact that conditions promoting one also favor the other suggests related membrane active structural states. Here, a novel high throughput screening protocol is described that capitalizes on this correlation to identify compounds that target membrane active species. Applied to a small library of 960 known bioactive compounds, we are able to report identification of 37 compounds of which 36 were not previously reported as active toward IAPP fiber formation. Several compounds tested in secondary cell viability assays also demonstrate cytoprotective effects. It is a general observation that peptide induced toxicity in several amyloid diseases (such as Alzhiemer's and Parkinson's) involves a membrane bound, preamyloid oligomeric species. Our data here suggest that a screening protocol based on lipid-catalyzed assembly will find mechanistically informative small molecule hits in this subclass of amyloid diseases.

    Original languageEnglish (US)
    Pages (from-to)1341-1348
    Number of pages8
    JournalProtein Science
    Volume23
    Issue number10
    DOIs
    StatePublished - Oct 1 2014

    Fingerprint

    Islet Amyloid Polypeptide
    Amyloid
    Screening
    Lipids
    Molecules
    Membranes
    Toxicity
    Cells
    Lipid bilayers
    Fibers
    Poisons
    Depolarization
    Lipid Bilayers
    Cell membranes
    Libraries
    Pancreas
    Assays
    Cell Survival
    Cell Death
    Agglomeration

    Keywords

    • amylin
    • amyloid
    • high throughput screen
    • HTF
    • IAPP
    • lipids
    • small molecules
    • toxicity
    • Type 2 diabetes

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Medicine(all)

    Cite this

    Small molecule screening in context : Lipid-catalyzed amyloid formation. / Hebda, James A.; Magzoub, Mazin; Miranker, Andrew D.

    In: Protein Science, Vol. 23, No. 10, 01.10.2014, p. 1341-1348.

    Research output: Contribution to journalArticle

    Hebda, JA, Magzoub, M & Miranker, AD 2014, 'Small molecule screening in context: Lipid-catalyzed amyloid formation', Protein Science, vol. 23, no. 10, pp. 1341-1348. https://doi.org/10.1002/pro.2518
    Hebda, James A. ; Magzoub, Mazin ; Miranker, Andrew D. / Small molecule screening in context : Lipid-catalyzed amyloid formation. In: Protein Science. 2014 ; Vol. 23, No. 10. pp. 1341-1348.
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