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Nonsteroidal anti-inflammatory drug naproxen destabilizes A? amyloid fibrils: a molecular dynamics investigation.

ABSTRACT: Using implicit solvent model and replica exchange molecular dynamics, we examine the propensity of a nonsteroidal anti-inflammatory drug, naproxen, to interfere with A? fibril growth. We also compare the antiaggregation propensity of naproxen with that of ibuprofen. Naproxen's antiaggregation effect is influenced by two factors. Similar to ibuprofen, naproxen destabilizes binding of incoming A? peptides to the fibril due to direct competition between the ligands and the peptides for the same binding location on the fibril surface (the edge). However, in contrast to ibuprofen, naproxen binding also alters the conformational ensemble of A? monomers by promoting ?-structure. The second factor weakens naproxen's antiaggregation effect. These findings appear to explain the experimental observations, in which naproxen binds to the A? fibril with higher affinity than ibuprofen, yet produces weaker antiaggregation action.

SUBMITTER: Takeda T

PROVIDER: S-EPMC3034367 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Nonsteroidal anti-inflammatory drug naproxen destabilizes Aβ amyloid fibrils: a molecular dynamics investigation.

Takeda Takako T Kumar Rashmi R Raman E Prabhu EP Klimov Dmitri K DK

The journal of physical chemistry. B 20101027 46

Using implicit solvent model and replica exchange molecular dynamics, we examine the propensity of a nonsteroidal anti-inflammatory drug, naproxen, to interfere with Aβ fibril growth. We also compare the antiaggregation propensity of naproxen with that of ibuprofen. Naproxen's antiaggregation effect is influenced by two factors. Similar to ibuprofen, naproxen destabilizes binding of incoming Aβ peptides to the fibril due to direct competition between the ligands and the peptides for the same bin ...[more]

PMID: 20979356

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Project description:BACKGROUND:Lipid transfer protein (LTP), an abundant protein in fruits, vegetables, and nuts, is a common food allergen in Mediterranean areas causing diverse allergic reactions. Approximately 40% of food-related anaphylaxis induced by LTPs requires nonsteroidal anti-inflammatory drugs (NSAIDs) as a triggering cofactor. OBJECTIVE:We sought to better understand the determinants of NSAID-dependent and NSAID-independent LTP-induced anaphylaxis (LTP-A). METHODS:Selection of patients was based on a proved clinical history of NSAID-dependent or NSAID-independent anaphylaxis to LTPs, positive skin prick test response to LTPs, and serum LTP IgE. Whole-transcriptome (RNA sequencing) analysis of blood cells from 14 patients with NSAID-related LTP-A (NSAID-LTP-A), 7 patients with LTP-A, and 13 healthy control subjects was performed to identify distinct gene expression signatures. RESULTS:Expression of genes regulating gastrointestinal epithelial renewal was altered in both patient sets, particularly in those with LTP-A, who also presented with gene expression profiles characteristic of an inflammatory syndrome. These included altered B-cell pathways, increased neutrophil activation markers, and increased reactive oxygen species levels. Increased expression of the IgG receptor (CD64) in patients with LTP-A was mirrored by the presence of LTP-specific IgG1 and IgG3. Conversely, patients with NSAID-LTP-A were characterized by reduced expression of IFN-?-regulated genes and IFN-? levels, as well as upregulated expression of adenosine receptor 3 (ADORA3) and genes related to adenosine metabolism. CONCLUSIONS:Gene ontology analysis suggests disturbances in gut epithelial homeostasis in both groups with LTP-A, with potential integrity breaches in patients with LTP-A that might explain their distinct inflammatory signatures. Differential regulation in patients with LTP-A and those with NSAID-LTP-A of the IFN-? pathway, IgG receptors, and ADORA3 might provide the pathogenic basis of their distinct responses.

Dataset Information

Nonsteroidal anti-inflammatory drug naproxen destabilizes A? amyloid fibrils: a molecular dynamics investigation.

Publications

Nonsteroidal anti-inflammatory drug naproxen destabilizes Aβ amyloid fibrils: a molecular dynamics investigation.

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