Intramolecular Proton and Charge Transfer of Pyrene‐based <i>trans</i>‐Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins

Zhang, Jun; Wang, Jun; Sandberg, Alexander; Wu, Xiongyu; Nyström, Sofie; LeVine, Harry; Konradsson, Peter; Hammarström, Per; Durbeej, Bo; Lindgren, Mikael

doi:10.1002/cphc.201800823

Cited by 12 publications

(15 citation statements)

References 44 publications

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“…Previously, we showed that bovine insulin could form two types of amyloids under different solvent conditions:toxic fibrils and less toxic filaments, which formed in the presence of a reducing reagent 12 . Certain amyloid-specific luminescent-conjugated oligothiophenes (LCOs) such as pFTAA, and benzothiadiazole (BTD) derivatives 13 , could discriminate between the two different insulin amyloids 14,15,16 . We also demonstrate that human insulin can form toxic amyloid from intact insulin ((i)-amyloid), and less toxic amyloid formed by insulin treated with reducing reagents ((r)-amyloid); we then used these human insulin amyloids as a model of insulin balls.…”

Section: Introductionmentioning

confidence: 99%

Degradation of Insulin Amyloid by Antibiotic Minocycline and Formation of Toxic Intermediates

Mori

Yuzu

Lobsiger

et al. 2021

Preprint

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Insulin balls, localized insulin amyloids formed at subcutaneous insulin-injection sites in patients with diabetes, cause poor glycemic control owing to impairments in insulin absorption. Our previous study has shown that some insulin balls are cytotoxic, but others are not, implying amyloid polymorphism. Interestingly, the patient with toxic insulin balls had been treated with antibiotic minocycline, suggesting a possible relationship between toxicity of insulin balls and minocycline. However, the direct effect of minocycline on the structure and cytotoxicity of the insulin amyloid is still unclear. Herein, we demonstrated that that minocycline at physiological concentrations induced degradation of insulin amyloids formed from human insulin and insulin drug preparations used for diabetes patients. Interestingly, the process involved the initial appearance of the toxic species, which subsequently changed into less-toxic species. It is also shown that the structure of the toxic species was similar to that of sonicated fragments of human insulin amyloids. Our study shed new light on the clarification of the revelation of insulin balls and the development of the insulin analogs for diabetes therapy.

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Section: Introductionmentioning

confidence: 99%

Degradation of Insulin Amyloid by Antibiotic Minocycline and Formation of Toxic Intermediates

Mori

Yuzu

Lobsiger

et al. 2021

Preprint

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“…S2 ), supporting that the droplets are filled with amyloids 35 . It is plausible that PK could bind to the insulin amyloid in the droplet since pyrene and its derivatives were shown to bind to various amyloids with hydrophobic interactions 36 , 37 .…”

Section: Resultsmentioning

confidence: 99%

Differences in interaction lead to the formation of different types of insulin amyloid

Mori

Kawakami

Niko

et al. 2022

Sci Rep

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Insulin balls, localized insulin amyloids formed at the site of repeated insulin injections in patients with diabetes, cause poor glycemic control and cytotoxicity. Our previous study has shown that insulin forms two types of amyloids; toxic amyloid formed from the intact insulin ((i)-amyloid) and less-toxic amyloid formed in the presence of the reducing reagent TCEP ((r)-amyloid), suggesting insulin amyloid polymorphism. However, the differences in the formation mechanism and cytotoxicity expression are still unclear. Herein, we demonstrate that the liquid droplets, which are stabilized by electrostatic interactions, appear only in the process of toxic (i)-amyloid formation, but not in the less-toxic (r)-amyloid formation process. The effect of various additives such as arginine, 1,6-hexanediol, and salts on amyloid formation was also examined to investigate interactions that are important for amyloid formation. Our results indicate that the maturation processes of these two amyloids were significantly different, whereas the nucleation by hydrophobic interactions was similar. These results also suggest the difference in the formation mechanism of two different insulin amyloids is attributed to the difference in the intermolecular interactions and could be correlated with the cytotoxicity.

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“…We are using TTR as a research platform to understand small-molecule recognition and binding specificity in our work to facilitate these efforts. , While the structure of TTR was originally solved in 1978 and hundreds of structures of TTR variants and TTR complexes are present in the protein database (PDB), the binding modes of TTR ligands are still a matter of intense research: Recently, a quinoline-derived D–A–D-type fluorescent probe was utilized by Sun et al to study its binding to wild-type TTR, while previous work by some of us has identified a pyrene-based trans-stilbene ligand with a salicylic acid moiety (Py1SA) as an amyloid fibril probe for several different amyloid proteins. Py1SA is an amyloid fluorophore containing a combination of a salicylic acid trans-stilbene conjugated with a pyrene . Its design was based on the pan-amyloid Congo red analogue X-34 and the pyrene moiety from its extensive fluorescence lifetime.…”

Section: Introductionmentioning

confidence: 99%

Binding of a Pyrene-Based Fluorescent Amyloid Ligand to Transthyretin: A Combined Crystallographic and Molecular Dynamics Study

Thi Minh,

Begum,

Zhang

et al. 2023

J. Phys. Chem. B

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Misfolding and aggregation of transthyretin (TTR) cause several amyloid diseases. Besides being an amyloidogenic protein, TTR has an affinity for bicyclic small-molecule ligands in its thyroxine (T4) binding site. One class of TTR ligands are transstilbenes. The trans-stilbene scaffold is also widely applied for amyloid fibril-specific ligands used as fluorescence probes and as positron emission tomography tracers for amyloid detection and diagnosis of amyloidosis. We have shown that native tetrameric TTR binds to amyloid ligands based on the trans-stilbene scaffold providing a platform for the determination of high-resolution structures of these important molecules bound to protein. In this study, we provide spectroscopic evidence of binding and X-ray crystallographic structure data on tetrameric TTR complex with the fluorescent salicylic acid-based pyrene amyloid ligand (Py1SA), an analogue of the Congo red analogue X-34. The ambiguous electron density from the X-ray diffraction, however, did not permit Py1SA placement with enough confidence likely due to partial ligand occupancy. Instead, the preferred orientation of the Py1SA ligand in the binding pocket was determined by molecular dynamics and umbrella sampling approaches. We find a distinct preference for the binding modes with the salicylic acid group pointing into the pocket and the pyrene moiety outward to the opening of the T4 binding site. Our work provides insight into TTR binding mode preference for trans-stilbene salicylic acid derivatives as well as a framework for determining structures of TTR−ligand complexes.

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Intramolecular Proton and Charge Transfer of Pyrene‐based trans‐Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins

Cited by 12 publications

References 44 publications

Degradation of Insulin Amyloid by Antibiotic Minocycline and Formation of Toxic Intermediates

Degradation of Insulin Amyloid by Antibiotic Minocycline and Formation of Toxic Intermediates

Differences in interaction lead to the formation of different types of insulin amyloid

Binding of a Pyrene-Based Fluorescent Amyloid Ligand to Transthyretin: A Combined Crystallographic and Molecular Dynamics Study

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