Inhibition of islet amyloid polypeptide aggregation and associated cytotoxicity by nonsteroidal anti-inflammatory drugs

Fortin, Jessica S.; Benoit‐Biancamano, Marie‐Odile

doi:10.1139/cjpp-2015-0117

Cited by 13 publications

(10 citation statements)

References 46 publications

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“…According to the molecular docking studies, the chaperones interact with the region comprised between amino acids 11 to 28, by hydrogen bonds, hydrophobic interactions, and by Van der Waals forces. This region is one of those reported by Eisenberg et al [ 36 , 37 ], which is involved in the formation of the steric zipper. All chaperones engage strongly through the interactions π∙∙∙π stacking with key amino acid Phe15.…”

Section: Discussionmentioning

confidence: 52%

“…Hence, this protein is a target to find breaking agents of the β conformer. Eisenberg et al [ 36 ] described that the IAPP molecules are capable of adopting a dimeric structure and that this structure is an intermediate on the pathway to fibrillation. Additionally, in the study, they suggest that the non-fibrillary state of hIAPP 1–37 can form dimers with the two IAPP molecules interacting at helical interfaces centred at the aromatic stack of two Phe15 residue [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

“…Eisenberg et al [ 36 ] described that the IAPP molecules are capable of adopting a dimeric structure and that this structure is an intermediate on the pathway to fibrillation. Additionally, in the study, they suggest that the non-fibrillary state of hIAPP 1–37 can form dimers with the two IAPP molecules interacting at helical interfaces centred at the aromatic stack of two Phe15 residue [ 36 ]. In others reports, Eisenberg et al studied the influence of different sequence fragments of amino acid (a.a) on the conformational polymorphism of the hIAPP 1–37 peptide [ 37 ].…”

Section: Resultsmentioning

confidence: 99%

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Diabetes Drug Discovery: hIAPP1–37 Polymorphic Amyloid Structures as Novel Therapeutic Targets

et al. 2018

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Human islet amyloid peptide (hIAPP1–37) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of hIAPP1–37) required to meet the treatment challenges of diabetes. We used a cross-functional approach that combines in silico and in vitro biochemical and biophysical methods to study the hIAPP1–37 aggregation-oligomerization process as to reveal novel potential anti-diabetic drugs. The family of pharmaco-chaperones are modulators of the oligomerization and fibre formation of hIAPP1–37. When they interact with the amino acid in the amyloid-like steric zipper zone, they inhibit and/or delay the aggregation-oligomerization pathway by binding and stabilizing several amyloid structures of hIAPP1–37. Moreover, they can protect cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP1–37 oligomers. The modulation of proteostasis by the family of pharmaco-chaperones A–F is a promising potential approach to limit the onset and progression of diabetes and its comorbidities.

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Section: Discussionmentioning

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Diabetes Drug Discovery: hIAPP1–37 Polymorphic Amyloid Structures as Novel Therapeutic Targets

et al. 2018

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“…Until recently, NSAIDs including diclofenac, phenylbutazone, meloxicam, piroxicam, tenoxicam, and sulindac have been reported to inhibit hIAPP aggregation by either inhibiting the fibrilization or/and oligomerization. Among them, meloxicam only protected INS-1 cells from hIAPP-induced toxicity at low concentrations of 25 μM, while other drugs achieved better cell protection effects at both 25 and 50 μM . Since hIAPP deposition is related to β-cell dysfunction, several hypoglycemic drugs such as repaglinide, glyburide, and troglitazone have demonstrated their potential for the treatment of T2D by delaying and reducing the formation of β-sheet structures and amyloid fibrils of hIAPP, as well as protecting INS-1 cell viability .…”

Section: Hiapp Aggregation Inhibitorsmentioning

confidence: 99%

Introduction and Fundamentals of Human Islet Amyloid Polypeptide Inhibitors

Tang

Zhang

et al. 2020

ACS Appl. Bio Mater.

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Type 2 diabetes (T2D) is a common protein misfolding disease (PMD), and its pathogenesis is considered to be tightly associated with the aggregation of the disease-causative hIAPP (or amylin). Numerous studies have shown a possible pathological link between hIAPP aggregation and β-cell death; thus, different-level strategies from basic research to clinical bench applications have been applied to discover and design different types of inhibitors for preventing hIAPP aggregation and toxicity. This review surveys recent and important advances of hIAPP aggregation inhibitors in the context of amyloid aggregation, toxicity, and inhibition. Many hIAPP inhibitors have been explored to exert different inhibitory functions on hIAPP aggregation via different pathways. A further overview of molecular simulations of inhibitor–hIAPP systems highlights some consensus binding sequences and structures of hIAPP for different inhibitors, which provide molecular insights into well-defined binding targets and binding-induced inhibition mechanisms for structural-based design of hIAPP inhibitors. In a broader view, while anti-aggregation inhibitors hold substantial promise in the prevention of PMDs, many challenges still remain and need to be addressed for advancing our fundamental understanding of amyloid aggregation and practical design of clinically relevant inhibitors to treat PMDs.

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“…Little work has been devoted to the study, at a molecular level, of hIAPP oligomerization from the earliest stages of the process, while it would give insights on the parameters triggering or stopping this pathological process. In vitro studies investigating this pathological process have been based mostly on fluorescence spectrophotometry using ThT as a β-sheet probe [12][13][14][15][16][17][18][19], size exclusion liquid chromatography [18], SDS-PAGE [18,20], NMR [8,21,22], or IMS-MS [15,19,[23][24][25][26]. However, these studies have provided different (if not conflicting) results, in terms of observed species (size and conformations of hIAPP) and of kinetics rate of the oligomerization process.…”

Section: Introductionmentioning

confidence: 99%

Evidence for different in vitro oligomerization behaviors of synthetic hIAPP obtained from different sources

et al. 2020

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Type 2 diabetes is characterized by the aggregation of human islet amyloid polypeptide (hIAPP), from monomer to amyloid deposits that are made of insoluble fibrils. Discrepancies concerning the nature of formed species or oligomerization kinetics among reported in vitro studies on hIAPP aggregation process have been highlighted. In this work, we investigated if the sample itself could be at the origin of those observed differences. To this aim, four hIAPP samples obtained from three different sources or suppliers have been analyzed and compared by ThT fluorescence spectroscopy and by two recently developed techniques, capillary electrophoresis (CE), and ESI-IMS-QToF-MS. Lots provided by the same supplier were shown to be very similar whatever the analytical technique used to characterize them. In contrast, several critical differences could be pointed out for hIAPP provided by different suppliers. We demonstrated that in several samples, some oligomerized peptides (e.g., dimer) were already present upon reception. Purity was also different, and the proneness of the peptide solution to form fibrils in vitro within 24 h could vary considerably from one sample source to another but not from lot to lot of the same source. All those results demonstrate that the initial state of conformation, oligomerization, and quality of the hIAPP can greatly impact the aggregation kinetics, and thus the information provided by these in vitro tests. Finally, a careful selection of the peptide batch and source is mandatory to perform relevant in vitro studies on hIAPP oligomerization and to screen new molecules modulating this pathological process.

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Inhibition of islet amyloid polypeptide aggregation and associated cytotoxicity by nonsteroidal anti-inflammatory drugs

Cited by 13 publications

References 46 publications

Diabetes Drug Discovery: hIAPP1–37 Polymorphic Amyloid Structures as Novel Therapeutic Targets

Diabetes Drug Discovery: hIAPP1–37 Polymorphic Amyloid Structures as Novel Therapeutic Targets

Introduction and Fundamentals of Human Islet Amyloid Polypeptide Inhibitors

Evidence for different in vitro oligomerization behaviors of synthetic hIAPP obtained from different sources

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