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Inhibition of anthrax lethal factor by curcumin and chemically modified curcumin derivatives.

Antonelli AC, Zhang Y, Golub LM, Johnson F, Simon SR - J Enzyme Inhib Med Chem (2013)

Bottom Line: Curcumin (diferuloylmethane), the active ingredient in the eastern spice turmeric (Curcuma longa), has been shown to inhibit the activities of numerous enzymes and signaling molecules involved in cancer, bacterial and viral infections and inflammatory diseases.Curcumin (Compound 1) appears to inhibit the catalytic activity of LF through a mixture of inhibitory mechanisms, without significant compromise to the binding of oligopeptide substrates, and one CMC derivative in particular, Compound 3 (4-phenylaminocarbonylbis-demethoxycurcumin), is capable of inhibiting LF with potency comparable with the parent compound, while also showing improved solubility and stability.The quantitative reduction in catalytic activity achieved by the different CMC derivatives appears to be a function of the proportion of the multiple mechanisms through which they inhibit the enzyme.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology .

ABSTRACT
Curcumin (diferuloylmethane), the active ingredient in the eastern spice turmeric (Curcuma longa), has been shown to inhibit the activities of numerous enzymes and signaling molecules involved in cancer, bacterial and viral infections and inflammatory diseases. We have investigated the inhibitory activities of curcumin and chemically modified curcumin (CMC) derivatives toward lethal factor (LF), the proteolytic component of anthrax toxin produced by the bacterium Bacillus anthracis. Curcumin (Compound 1) appears to inhibit the catalytic activity of LF through a mixture of inhibitory mechanisms, without significant compromise to the binding of oligopeptide substrates, and one CMC derivative in particular, Compound 3 (4-phenylaminocarbonylbis-demethoxycurcumin), is capable of inhibiting LF with potency comparable with the parent compound, while also showing improved solubility and stability. The quantitative reduction in catalytic activity achieved by the different CMC derivatives appears to be a function of the proportion of the multiple mechanisms through which they inhibit the enzyme.

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(A) Lethal factor activity as measured by fluorescence generated over time. 100 nM lethal factor, 3 μM substrate and 20 μM inhibitors were used uniformly. Assay buffer was used in place of inhibitor as a control. (B) Percent residual activity of 100 nM lethal factor and 3 μM substrate after incubation with 20 μM inhibitors. All experiments were performed in triplicate. R2 values for all data exceeded 0.99, as determined by Levenberg–Marquardt linear regression analysis, indicating a high level of goodness-of-fit.
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f2: (A) Lethal factor activity as measured by fluorescence generated over time. 100 nM lethal factor, 3 μM substrate and 20 μM inhibitors were used uniformly. Assay buffer was used in place of inhibitor as a control. (B) Percent residual activity of 100 nM lethal factor and 3 μM substrate after incubation with 20 μM inhibitors. All experiments were performed in triplicate. R2 values for all data exceeded 0.99, as determined by Levenberg–Marquardt linear regression analysis, indicating a high level of goodness-of-fit.

Mentions: Curcumin (Compound 1) and the CMCs we tested, with the exception of Compound 2, were all found to inhibit LF peptidolytic activity in a dose-dependent fashion (Figure 2). The linear time course of the reactions indicates that neither the assay conditions nor the extended presence of the inhibitor had any denaturing effect on the enzyme, and thus that the data acquired do not reflect progressive irreversible inactivation. R2 values for all data exceeded 0.99, as determined by Levenberg–Marquardt linear regression analysis, indicating a high level of goodness-of-fit.Figure 2.


Inhibition of anthrax lethal factor by curcumin and chemically modified curcumin derivatives.

Antonelli AC, Zhang Y, Golub LM, Johnson F, Simon SR - J Enzyme Inhib Med Chem (2013)

(A) Lethal factor activity as measured by fluorescence generated over time. 100 nM lethal factor, 3 μM substrate and 20 μM inhibitors were used uniformly. Assay buffer was used in place of inhibitor as a control. (B) Percent residual activity of 100 nM lethal factor and 3 μM substrate after incubation with 20 μM inhibitors. All experiments were performed in triplicate. R2 values for all data exceeded 0.99, as determined by Levenberg–Marquardt linear regression analysis, indicating a high level of goodness-of-fit.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196590&req=5

f2: (A) Lethal factor activity as measured by fluorescence generated over time. 100 nM lethal factor, 3 μM substrate and 20 μM inhibitors were used uniformly. Assay buffer was used in place of inhibitor as a control. (B) Percent residual activity of 100 nM lethal factor and 3 μM substrate after incubation with 20 μM inhibitors. All experiments were performed in triplicate. R2 values for all data exceeded 0.99, as determined by Levenberg–Marquardt linear regression analysis, indicating a high level of goodness-of-fit.
Mentions: Curcumin (Compound 1) and the CMCs we tested, with the exception of Compound 2, were all found to inhibit LF peptidolytic activity in a dose-dependent fashion (Figure 2). The linear time course of the reactions indicates that neither the assay conditions nor the extended presence of the inhibitor had any denaturing effect on the enzyme, and thus that the data acquired do not reflect progressive irreversible inactivation. R2 values for all data exceeded 0.99, as determined by Levenberg–Marquardt linear regression analysis, indicating a high level of goodness-of-fit.Figure 2.

Bottom Line: Curcumin (diferuloylmethane), the active ingredient in the eastern spice turmeric (Curcuma longa), has been shown to inhibit the activities of numerous enzymes and signaling molecules involved in cancer, bacterial and viral infections and inflammatory diseases.Curcumin (Compound 1) appears to inhibit the catalytic activity of LF through a mixture of inhibitory mechanisms, without significant compromise to the binding of oligopeptide substrates, and one CMC derivative in particular, Compound 3 (4-phenylaminocarbonylbis-demethoxycurcumin), is capable of inhibiting LF with potency comparable with the parent compound, while also showing improved solubility and stability.The quantitative reduction in catalytic activity achieved by the different CMC derivatives appears to be a function of the proportion of the multiple mechanisms through which they inhibit the enzyme.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology .

ABSTRACT
Curcumin (diferuloylmethane), the active ingredient in the eastern spice turmeric (Curcuma longa), has been shown to inhibit the activities of numerous enzymes and signaling molecules involved in cancer, bacterial and viral infections and inflammatory diseases. We have investigated the inhibitory activities of curcumin and chemically modified curcumin (CMC) derivatives toward lethal factor (LF), the proteolytic component of anthrax toxin produced by the bacterium Bacillus anthracis. Curcumin (Compound 1) appears to inhibit the catalytic activity of LF through a mixture of inhibitory mechanisms, without significant compromise to the binding of oligopeptide substrates, and one CMC derivative in particular, Compound 3 (4-phenylaminocarbonylbis-demethoxycurcumin), is capable of inhibiting LF with potency comparable with the parent compound, while also showing improved solubility and stability. The quantitative reduction in catalytic activity achieved by the different CMC derivatives appears to be a function of the proportion of the multiple mechanisms through which they inhibit the enzyme.

Show MeSH
Related in: MedlinePlus