title: Monitoring and inhibition of insulin fibrillation by a small organic fluorogen with aggregation-induced emission characteristics.
abstract: Amyloid fibrillation of proteins is associated with a great variety of pathologic conditions. Development of new molecules that can monitor amyloidosis kinetics and inhibit fibril formation is of great diagnostic and therapeutic value. In this work, we have developed a biocompatible molecule that functions as an ex situ monitor and an in situ inhibitor for protein fibrillation, using insulin as a model protein. 1,2-Bis[4-(3-sulfonatopropoxyl)phenyl]-1,2-diphenylethene salt (BSPOTPE) is nonemissive when it is dissolved with native insulin in an incubation buffer but starts to fluoresce when it is mixed with preformed insulin fibril, enabling ex situ monitoring of amyloidogenesis kinetics and high-contrast fluorescence imaging of protein fibrils. Premixing BSPOTPE with insulin, on the other hand, inhibits the nucleation process and impedes the protofibril formation. Increasing the dose of BSPOTPE boosts its inhibitory potency. Theoretical modeling using molecular dynamics simulations and docking reveals that BSPOTPE is prone to binding to partially unfolded insulin through hydrophobic interaction of the phenyl rings of BSPOTPE with the exposed hydrophobic residues of insulin. Such binding is assumed to have stabilized the partially unfolded insulin and obstructed the formation of the critical oligomeric species in the protein fibrillogenesis process.
authors.affiliation: Department of Chemistry, State Key Laboratory of Molecular Neuroscience, Institute of Molecular Functional Materials, The Hong Kong University of Science & Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Yuning
authors.initials: Y
authors.lastname: Hong
authors.forename: Luming
authors.initials: L
authors.lastname: Meng
authors.forename: Sijie
authors.initials: S
authors.lastname: Chen
authors.forename: Chris Wai Tung
authors.initials: CW
authors.lastname: Leung
authors.forename: Lin-Tai
authors.initials: LT
authors.lastname: Da
authors.forename: Mahtab
authors.initials: M
authors.lastname: Faisal
authors.forename: Daniel-Adriano
authors.initials: DA
authors.lastname: Silva
authors.forename: Jianzhao
authors.initials: J
authors.lastname: Liu
authors.forename: Jacky Wing Yip
authors.initials: JW
authors.lastname: Lam
authors.forename: Xuhui
authors.initials: X
authors.lastname: Huang
authors.forename: Ben Zhong
authors.initials: BZ
authors.lastname: Tang
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000686:Amyloidosis / Q000175:diagnosis; D000818:Animals; D002417:Cattle; D007328:Insulin / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D013050:Spectrometry, Fluorescence; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000682:Amyloid; D007328:Insulin; D013267:Stilbenes; C554024:sodium 1,2-bis(4-(3-sulfonatopropoxyl)phenyl)-1,2-diphenylethene