title: Inhibition of islet amyloid polypeptide fibril formation: a potential role for heteroaromatic interactions.
abstract: The formation of amyloid fibril is associated with major human diseases, including Alzheimer's disease, prion diseases, and type 2 diabetes. Methods for efficient inhibition of amyloid fibril formation are therefore highly clinically important. A principal approach for the inhibition of amyloid formation is based on the use of modified molecular recognition elements. Here, we demonstrate efficient inhibition of amyloid formation of the type 2 diabetes-related human islet amyloid polypeptide (hIAPP) by a modified aromatic peptide fragment and a small aromatic polyphenol molecule. A molecular recognition assay using peptide array analysis suggested that molecular recognition between hIAPP and its core amyloidogenic module is mediated by aromatic rather than hydrophobic interactions. To study the possible effect of aromatic interactions on inhibition of hIAPP fibril formation, we have used peptide and small molecule inhibitors. The addition of a nonamyloidogenic peptide analogue of the core module NFGAILSS, in which phenylalanine was substituted with tyrosine (NYGAILSS), resulted in substantial inhibition of fibril formation by hIAPP. The inhibition was significantly stronger than the one achieved using a beta-sheet breaker-conjugated peptide NFGAILPP. On the basis of the molecular arrangement of the tyrosine-phenylalanine interaction, we suggest that the inhibition stems from the geometrical constrains of the heteroaromatic benzene-phenol interaction. In line with this notion, we demonstrate remarkable inhibition of hIAPP fibril formation and cytotoxicity toward pancreatic beta-cells by a small polyphenol molecule, the nontoxic phenol red compound. Taken together, our results provide further experimental support for the potential role of aromatic interactions in amyloid formation and establish a novel approach for its inhibition.
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Porat
authors.forename: Yariv
authors.initials: Y
authors.lastname: Mazor
authors.forename: Shimon
authors.initials: S
authors.lastname: Efrat
authors.forename: Ehud
authors.initials: E
authors.lastname: Gazit
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000633:toxicity / Q000648:ultrastructure; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D005419:Flavonoids / Q000494:pharmacology; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000633:toxicity / Q000648:ultrastructure; D010636:Phenols / Q000494:pharmacology; D010637:Phenolsulfonphthalein / Q000494:pharmacology; D010649:Phenylalanine / Q000235:genetics; D059808:Polyphenols; D011485:Protein Binding; D025941:Protein Interaction Mapping; D051381:Rats; D013050:Spectrometry, Fluorescence; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000682:Amyloid; D005419:Flavonoids; D006131:Growth Inhibitors; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; D010636:Phenols; D059808:Polyphenols; C117453:amylin (20-29); D014443:Tyrosine; D010649:Phenylalanine; D010637:Phenolsulfonphthalein