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Halogenation generates effective modulators of amyloid-Beta aggregation and neurotoxicity.

Wong HE, Irwin JA, Kwon I - PLoS ONE (2013)

Bottom Line: Halogenation of organic compounds plays diverse roles in biochemistry, including selective chemical modification of proteins and improved oral absorption/blood-brain barrier permeability of drug candidates.However, halogenation of either the xanthenes or benzoate ring of fluorescein substantially enhanced the inhibitory capacity on Aβ aggregation.To our knowledge, this is the first report demonstrating that halogenation of aromatic rings substantially enhance inhibitory capacities of small molecules on Aβ-associated neurotoxicity via Aβ aggregation modulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, University of Virginia, Charlottesville, VA, USA.

ABSTRACT
Halogenation of organic compounds plays diverse roles in biochemistry, including selective chemical modification of proteins and improved oral absorption/blood-brain barrier permeability of drug candidates. Moreover, halogenation of aromatic molecules greatly affects aromatic interaction-mediated self-assembly processes, including amyloid fibril formation. Perturbation of the aromatic interaction caused by halogenation of peptide building blocks is known to affect the morphology and other physical properties of the fibrillar structure. Consequently, in this article, we investigated the ability of halogenated ligands to modulate the self-assembly of amyloidogenic peptide/protein. As a model system, we chose amyloid-beta peptide (Aβ), which is implicated in Alzheimer's disease, and a novel modulator of Aβ aggregation, erythrosine B (ERB). Considering that four halogen atoms are attached to the xanthene benzoate group in ERB, we hypothesized that halogenation of the xanthene benzoate plays a critical role in modulating Aβ aggregation and cytotoxicity. Therefore, we evaluated the modulating capacities of four ERB analogs containing different types and numbers of halogen atoms as well as fluorescein as a negative control. We found that fluorescein is not an effective modulator of Aβ aggregation and cytotoxicity. However, halogenation of either the xanthenes or benzoate ring of fluorescein substantially enhanced the inhibitory capacity on Aβ aggregation. Such Aβ aggregation inhibition by ERB analogs except rose bengal correlated well to the inhibition of Aβ cytotoxicity. To our knowledge, this is the first report demonstrating that halogenation of aromatic rings substantially enhance inhibitory capacities of small molecules on Aβ-associated neurotoxicity via Aβ aggregation modulation.

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Chemical Structure of erythrosine B (ERB), eosin Y (EOY), eosin B (EOB), rose bengal (ROB), phloxine B (PHB), and fluorescein (FLN) at neutral pH.
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pone-0057288-g001: Chemical Structure of erythrosine B (ERB), eosin Y (EOY), eosin B (EOB), rose bengal (ROB), phloxine B (PHB), and fluorescein (FLN) at neutral pH.

Mentions: Herein, we have investigated whether halogenation of ligands can also affect self-assembly of amyloid-beta peptide (Aβ), which is implicated in Alzheimer’s disease (AD). A pathological hallmark of AD is the accumulation of insoluble protein aggregates, composed primarily of fibrillar Aβ aggregates. According to the revised amyloid-cascade hypothesis, certain types of soluble Aβ oligomers and protofibrils are more toxic than Aβ fibrils and correlate well with dementia [14], [15], [16], [17]. Therefore, modulation of Aβ aggregation using small molecules is considered a promising way to eliminate Aβ associated toxicity [3], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. We recently reported that red food dye erythrosine B (ERB) is a novel modulator of Aβ-aggregation in vitro and Aβ neurotoxicity [33]. The good biocompatibility and possibility of systemic administration make ERB an attractive inhibitor of Aβ neurotoxicity [34], [35]. Considering that ERB has multiple aromatic rings attached to four electronegative halogen atoms (Figure 1), we hypothesize that the modulatory capacity of ERB on Aβ aggregation is attributed to halogen atoms. In order to validate our hypothesis that halogen atoms are key chemical structures for Aβ aggregation modulation, we evaluated the modulating capacities of four ERB congeners containing different type and number of halogen atoms, eosin Y (EOY), eosin B (EOB), rose bengal (ROB), and phloxine B (PHB) (Figure 1). As a negative control, we also evaluated fluorescein (FLN), which has the same xanthene benzoate backbone as ERB but lacks a halogen atom. If halogenation of aromatic rings is indeed effective in modulating Aβ aggregation and cytotoxicity, it will enhance our understanding of molecular mechanism of amyloid formation and facilitate discovery and design of a new series of halogenated small molecule modulators of amyloidogenic peptides/proteins.


Halogenation generates effective modulators of amyloid-Beta aggregation and neurotoxicity.

Wong HE, Irwin JA, Kwon I - PLoS ONE (2013)

Chemical Structure of erythrosine B (ERB), eosin Y (EOY), eosin B (EOB), rose bengal (ROB), phloxine B (PHB), and fluorescein (FLN) at neutral pH.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585355&req=5

pone-0057288-g001: Chemical Structure of erythrosine B (ERB), eosin Y (EOY), eosin B (EOB), rose bengal (ROB), phloxine B (PHB), and fluorescein (FLN) at neutral pH.
Mentions: Herein, we have investigated whether halogenation of ligands can also affect self-assembly of amyloid-beta peptide (Aβ), which is implicated in Alzheimer’s disease (AD). A pathological hallmark of AD is the accumulation of insoluble protein aggregates, composed primarily of fibrillar Aβ aggregates. According to the revised amyloid-cascade hypothesis, certain types of soluble Aβ oligomers and protofibrils are more toxic than Aβ fibrils and correlate well with dementia [14], [15], [16], [17]. Therefore, modulation of Aβ aggregation using small molecules is considered a promising way to eliminate Aβ associated toxicity [3], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. We recently reported that red food dye erythrosine B (ERB) is a novel modulator of Aβ-aggregation in vitro and Aβ neurotoxicity [33]. The good biocompatibility and possibility of systemic administration make ERB an attractive inhibitor of Aβ neurotoxicity [34], [35]. Considering that ERB has multiple aromatic rings attached to four electronegative halogen atoms (Figure 1), we hypothesize that the modulatory capacity of ERB on Aβ aggregation is attributed to halogen atoms. In order to validate our hypothesis that halogen atoms are key chemical structures for Aβ aggregation modulation, we evaluated the modulating capacities of four ERB congeners containing different type and number of halogen atoms, eosin Y (EOY), eosin B (EOB), rose bengal (ROB), and phloxine B (PHB) (Figure 1). As a negative control, we also evaluated fluorescein (FLN), which has the same xanthene benzoate backbone as ERB but lacks a halogen atom. If halogenation of aromatic rings is indeed effective in modulating Aβ aggregation and cytotoxicity, it will enhance our understanding of molecular mechanism of amyloid formation and facilitate discovery and design of a new series of halogenated small molecule modulators of amyloidogenic peptides/proteins.

Bottom Line: Halogenation of organic compounds plays diverse roles in biochemistry, including selective chemical modification of proteins and improved oral absorption/blood-brain barrier permeability of drug candidates.However, halogenation of either the xanthenes or benzoate ring of fluorescein substantially enhanced the inhibitory capacity on Aβ aggregation.To our knowledge, this is the first report demonstrating that halogenation of aromatic rings substantially enhance inhibitory capacities of small molecules on Aβ-associated neurotoxicity via Aβ aggregation modulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, University of Virginia, Charlottesville, VA, USA.

ABSTRACT
Halogenation of organic compounds plays diverse roles in biochemistry, including selective chemical modification of proteins and improved oral absorption/blood-brain barrier permeability of drug candidates. Moreover, halogenation of aromatic molecules greatly affects aromatic interaction-mediated self-assembly processes, including amyloid fibril formation. Perturbation of the aromatic interaction caused by halogenation of peptide building blocks is known to affect the morphology and other physical properties of the fibrillar structure. Consequently, in this article, we investigated the ability of halogenated ligands to modulate the self-assembly of amyloidogenic peptide/protein. As a model system, we chose amyloid-beta peptide (Aβ), which is implicated in Alzheimer's disease, and a novel modulator of Aβ aggregation, erythrosine B (ERB). Considering that four halogen atoms are attached to the xanthene benzoate group in ERB, we hypothesized that halogenation of the xanthene benzoate plays a critical role in modulating Aβ aggregation and cytotoxicity. Therefore, we evaluated the modulating capacities of four ERB analogs containing different types and numbers of halogen atoms as well as fluorescein as a negative control. We found that fluorescein is not an effective modulator of Aβ aggregation and cytotoxicity. However, halogenation of either the xanthenes or benzoate ring of fluorescein substantially enhanced the inhibitory capacity on Aβ aggregation. Such Aβ aggregation inhibition by ERB analogs except rose bengal correlated well to the inhibition of Aβ cytotoxicity. To our knowledge, this is the first report demonstrating that halogenation of aromatic rings substantially enhance inhibitory capacities of small molecules on Aβ-associated neurotoxicity via Aβ aggregation modulation.

Show MeSH
Related in: MedlinePlus