Targeting insulin amyloid assembly by small aromatic molecules: Toward rational design of aggregation inhibitors

Levy‐Sakin, Michal; Shreberk, Michal; Daniel, Yael; Gazit, Ehud

doi:10.4161/isl.1.3.9609

Cited by 53 publications

(71 citation statements)

References 43 publications

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“…There has been a report about the unawaited effect of small aromatic compounds that enhance amyloid formation in insulin (in contrast with compounds containing multiple rings). This effect is especially remarkable for benzene and phenol which result in the formation of more compact fibrils (26). Thus, the unsubstituted benzene component of ligand no.…”

Section: Resultsmentioning

confidence: 99%

Benzofuranone Derivatives as Effective Small Molecules Related to Insulin Amyloid Fibrillation: A Structure–Function Study

et al. 2011

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Amyloids are protein fibrils of nanometer size resulting from protein self-assembly. They have been shown to be associated with a wide variety of diseases such as Alzheimer's and Parkinson's and may contribute to various other pathological conditions, known as amyloidoses. Insulin is prone to form amyloid fibrils under slightly destabilizing conditions in vitro and may form amyloid structures when subcutaneously injected into patients with diabetes. There is a great deal of interest in developing novel small molecule inhibitors of amyloidogenic processes, as potential therapeutic compounds. In this study, the effects of five new synthetic benzofuranone derivatives were investigated on the insulin amyloid formation process. Protein fibrillation was analyzed by thioflavin-T fluorescence, Congo red binding, circular dichroism, and electron microscopy. Despite high structural similarity, one of the five tested compounds was observed to enhance amyloid fibrillation, while the others inhibited the process when used at micromolar concentrations, which could make them interesting potential lead compounds for the design of therapeutic antiamyloidogenic compounds.

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Section: Resultsmentioning

confidence: 99%

Benzofuranone Derivatives as Effective Small Molecules Related to Insulin Amyloid Fibrillation: A Structure–Function Study

et al. 2011

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“…3) reveal that the small molecule PhCN slowed the progression of insulin fibril formation but did not entirely prevent it. In the literature, an electron donor-electron-acceptor complex of PhCN and Tyr in insulin was postulated, which is probably responsible for the inhibition33. Presumably, the insulin-PhCN interactions were too weak or occurred only in a tiny confined area and, thus, were insufficient to completely disable the β-sheet stacking of the peptide chains.…”

Section: Discussionmentioning

confidence: 99%

“…They are based mainly on stabilizing the native α-helix structure and/or destabilizing the non-native β-sheet structure12324. Potential inhibition was observed using natural polyphenols2325262728, flavonoids2930, carotenoids and vitamins3132, small aromatic molecules33, and co-solvents34353637. In those studies, the process was monitored in the bulk or after labelling with a fluorescent dye, whereas the morphology was independently imaged using AFM or SEM253037.…”

mentioning

confidence: 99%

High resolution spectroscopy reveals fibrillation inhibition pathways of insulin

Deckert‐Gaudig

Deckert

2016

Sci Rep

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Fibril formation implies the conversion of a protein’s native secondary structure and is associated with several neurodegenerative diseases. A better understanding of fibrillation inhibition and fibril dissection requires nanoscale molecular characterization of amyloid structures involved. Tip-enhanced Raman scattering (TERS) has already been used to chemically analyze amyloid fibrils on a sub-protein unit basis. Here, TERS in combination with atomic force microscopy (AFM), and conventional Raman spectroscopy characterizes insulin assemblies generated during inhibition and dissection experiments in the presence of benzonitrile, dimethylsulfoxide, quercetin, and β-carotene. The AFM topography indicates formation of filamentous or bead-like insulin self-assemblies. Information on the secondary structure of bulk samples and of single aggregates is obtained from standard Raman and TERS measurements. In particular the high spatial resolution of TERS reveals the surface conformations associated with the specific agents. The insulin aggregates formed under different inhibition and dissection conditions can show a similar morphology but differ in their β-sheet structure content. This suggests different aggregation pathways where the prevention of the β-sheet stacking of the peptide chains plays a major role. The presented approach is not limited to amyloid-related reasearch but can be readily applied to systems requiring extremely surface-sensitive characterization without the need of labels.

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“…Although monocyclic compounds such as phenolic acids were previously shown to be very poor inhibitors of aggregation (Reinke and Gestwicki, 2007), later studies revealed that monocyclic compounds could suppress amyloid assembly by interacting with oligomers, stabilizing their structure and conformation, thus inhibiting the transition to β-sheet structures (Levy-Sakin et al, 2009). It is therefore likely that phenolic acids, especially GA, act in a similar way, interacting with oligomers and stabilizing their structure through the -OH groups, preventing the transition to β-sheet-rich structures.…”

Section: Discussionmentioning

confidence: 99%

Structure activity relationship of phenolic acid inhibitors of Î±-synuclein fibril formation and toxicity

Ardah

Paleologou

et al. 2014

Front. Aging Neurosci.

103

100

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The aggregation of α-synuclein (α-syn) is considered the key pathogenic event in many neurological disorders such as Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, giving rise to a whole category of neurodegenerative diseases known as synucleinopathies. Although the molecular basis of α-syn toxicity has not been precisely elucidated, a great deal of effort has been put into identifying compounds that could inhibit or even reverse the aggregation process. Previous reports indicated that many phenolic compounds are potent inhibitors of α-syn aggregation. The aim of the present study was to assess the anti-aggregating effect of gallic acid (GA) (3,4,5-trihydroxybenzoic acid), a benzoic acid derivative that belongs to a group of phenolic compounds known as phenolic acids. By employing an array of biophysical and biochemical techniques and a cell-viability assay, GA was shown not only to inhibit α-syn fibrillation and toxicity but also to disaggregate preformed α-syn amyloid fibrils. Interestingly, GA was found to bind to soluble, non-toxic oligomers with no β-sheet content, and to stabilize their structure. The binding of GA to the oligomers may represent a potential mechanism of action. Additionally, by using structure activity relationship data obtained from fourteen structurally similar benzoic acid derivatives, it was determined that the inhibition of α-syn fibrillation by GA is related to the number of hydroxyl moieties and their position on the phenyl ring. GA may represent the starting point for designing new molecules that could be used for the treatment of PD and related disorders.

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Targeting insulin amyloid assembly by small aromatic molecules: Toward rational design of aggregation inhibitors

Cited by 53 publications

References 43 publications

Benzofuranone Derivatives as Effective Small Molecules Related to Insulin Amyloid Fibrillation: A Structure–Function Study

Benzofuranone Derivatives as Effective Small Molecules Related to Insulin Amyloid Fibrillation: A Structure–Function Study

High resolution spectroscopy reveals fibrillation inhibition pathways of insulin

Structure activity relationship of phenolic acid inhibitors of Î±-synuclein fibril formation and toxicity

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