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.

Highly Fluorescent and Photostable Probe for Long‐Term Bacterial Viability Assay Based on Aggregation‐Induced Emission

“…[ 17 ] We termed aggregation-induced emission (AIE) for this novel phenomenon and proposed restriction of intramolecular motions as the main cause for the AIE phenomenon. [ 18 , 19 ] In the past decade, the AIE luminogens have been successfully employed in a variety of biological applications such as for long-term cell tracking, [ 20 ] nonself-quenching DNA labeling, [ 21 ] inhibition of amyloid fi brillation, [ 22 ] monitoring of cell apoptosis, [ 23 ] etc. [ 24 -26 ] The AIE luminogens exhibit high quantum effi ciency, good biocompatibility, and appreciable photostability, which motivate us to further exploit its application in the thriving area of bacteria studies.…”

Insulin aggregation tracked by its intrinsic TRES

“…The use of these dyes has given a deeper understanding of protein fibrillation. The approaches used include conventional fluorescence spectra, 26 fluorescence decay, 27 and fluorescence correlation spectroscopy. 28 One of main findings observed in ThT-based experiments was ThT fluorescence intensity showing a sigmoidal function with negligible fluorescence intensity observed in the early stages, gradual increase over time and a plateau in the final stage.…”

New Chemo-/Biosensors with Silole and Tetraphenylethene Molecules Based on the Aggregation and Deaggregation Mechanism

“…Tang and co-workers found that 14 interacted differently with native and fibril insulin, thus leading to different degrees of fluorescence enhancement [26]. The probe 14 cannot bind with native insulin efficiently and remains nonemissive after mixing with native insulin in a buffered solution; however, 14 becomes strongly fluorescent after incubation with insulin fibril.…”