title: Targeting insulin amyloid assembly by small aromatic molecules: toward rational design of aggregation inhibitors.
abstract: Amyloid fibril formation is a common event in more than twenty human diseases and in some normal physiological processes. The mechanism of this ordered aggregation process and the molecular forces driving it are therefore of great importance. One of the strategies used in this field is targeting the fibrillization process by different factors, like, short peptides, organic molecules, etc. Here, we targeted insulin fibril formation by a range of small aromatic molecules, with different numbers of aromatic rings and various substituent groups. Using Thioflavin T fluorescence assay and transmission electron microscopy, we found that all dicyclic and tricyclic compounds in our screen were efficient inhibitors of insulin fibril formation. A common notion regarding amyloid inhibitors is that two functional groups are essentials for interfering with the amyloid formation process; a recognition motif and a bulky group for inducing a steric interference. However, here, we showed that some monocyclic compounds as small as toluene were also found to inhibit fibrillization. In addition, we found that substituent of benzene ring have a great influence on the inhibitory potency. Specifically, cyano, methyl and nitro groups increased the inhibitory potency. The results introduced here may contribute to future rational design of amyloid inhibitors.
authors.affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Levy-Sakin
authors.forename: Michal
authors.initials: M
authors.lastname: Shreberk
authors.forename: Yael
authors.initials: Y
authors.lastname: Daniel
authors.forename: Ehud
authors.initials: E
authors.lastname: Gazit
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D015195:Drug Design; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods; D010637:Phenolsulfonphthalein / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000517:prevention & control*; D055503:Protein Multimerization / Q000187:drug effects* / Q000502:physiology; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000682:Amyloid; D006841:Hydrocarbons, Aromatic; D007328:Insulin; D054852:Small Molecule Libraries; D010637:Phenolsulfonphthalein