Synthetic α-Helix Mimetics as Agonists and Antagonists of Islet Amyloid Polypeptide Aggregation

Authors

  • Ishu Saraogi,

    1. Department of Chemistry, Yale University, 225 Prospect Street, P.O. Box 208107, New Haven, CT 06520-8107 (USA), Fax: (+1) 203-432-6144
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    • These authors contributed equally to the work.

  • James A. Hebda,

    1. Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, P.O. Box 208114, New Haven, CT 06520-8114 (USA), Fax: (+1) 203-432-3104
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    • These authors contributed equally to the work.

  • Jorge Becerril,

    1. Department of Chemistry, Yale University, 225 Prospect Street, P.O. Box 208107, New Haven, CT 06520-8107 (USA), Fax: (+1) 203-432-6144
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  • Lara A. Estroff,

    1. Department of Chemistry, Yale University, 225 Prospect Street, P.O. Box 208107, New Haven, CT 06520-8107 (USA), Fax: (+1) 203-432-6144
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  • Andrew D. Miranker Prof.,

    1. Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, P.O. Box 208114, New Haven, CT 06520-8114 (USA), Fax: (+1) 203-432-3104
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  • Andrew D. Hamilton Prof.

    1. Department of Chemistry, Yale University, 225 Prospect Street, P.O. Box 208107, New Haven, CT 06520-8107 (USA), Fax: (+1) 203-432-6144
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  • We thank Prof. G. W. Brudvig for suggestions and Dr. C. Incarvito for assistance with X-ray crystallographic analysis. This work was supported by National Institutes of Health grants to A.D.H. (GM69850) and A.D.M. (NIDDK DK079829). J.A.H. was supported by a NRSA fellowship (AG031612).

Abstract

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Split personality: A series of oligoamide-based helix mimetics bind to a complementary helical motif in Islet amyloid polypeptide (IAPP), a protein implicated in the pathology of type II diabetes. These compounds accelerated IAPP amyloid formation under lipid-free conditions, but inhibited it under lipid-catalyzed conditions. hIAPP=human IAPP.

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