The broad-spectrum antiinfective drug artesunate interferes with the canonical nuclear factor kappa B (NF-κB) pathway by targeting RelA/p65

Hutterer, Corina; Niemann, Ina; Milbradt, Jens; Fröhlich, Tony; Reiter, Christoph; Kadioglu, Onat; Hanife, Bahsi; Zeitträger, Isabel; Wagner, Sabrina; Einsiedel, Jürgen; Gmeiner, Peter; Vogel, N. de; Wandinger, Sebastian K.; Godl, Klaus; Stamminger, Thomas; Efferth, Thomas; Tsogoeva, Svetlana B.; Marschall, Manfred

doi:10.1016/j.antiviral.2015.10.003

Cited by 49 publications

(61 citation statements)

References 44 publications

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“…To date, one mode of antiviral action has repeatedly been suggested and could experimentally be confirmed, namely the inhibition of the nuclear factor kappa B (NF‐κB) signaling pathway. A study by Hutterer and colleagues provided evidence based on a number of different methodologies that artesunic acid has the capacity to interfere with the canonical NF‐κB pathway by directly targeting RelA/p65 . This statement is further substantiated by novel data from our group to be published elsewhere.…”

Section: Resultsmentioning

confidence: 72%

“…[b] EC 50 values have been previously reported . [c] EC 50 value has been previously reported . [d] EC 50 value has been previously reported .…”

Section: Resultsmentioning

confidence: 97%

“…A series of further target validation experiments will be required to address this question and to clarify the role of binding proteins in the supposed complex mode of antiviral action. The fact that the formation of HCMV resistance against artemisinin‐related compounds could not be observed yet, makes it probable that primarily cellular proteins, possibly combined with one or more viral proteins, may represent a functionally relevant targeting network. In addition, cell type‐specific differences may also contribute to the compounds’ mechanistic complexity, which has to be unraveled in future studies.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of Artemisinin‐Derived Dimers, Trimers and Dendrimers: Investigation of Their Antimalarial and Antiviral Activities Including Putative Mechanisms of Action

Fröhlich

Hahn

Belmudes

et al. 2018

Chemistry A European J

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Generation of dimers, trimers and dendrimers of bioactive compounds is an approach that has recently been developed for the discovery of new potent drug candidates. Herein, we present the synthesis of new artemisinin-derived dimers and dendrimers and investigate their action against malaria parasite Plasmodium falciparum 3D7 strain and human cytomegalovirus (HCMV). Dimer 7 was the most active compound (EC 1.4 nm) in terms of antimalarial efficacy and was even more effective than the standard drugs dihydroartemisinin (EC 2.4 nm), artesunic acid (EC 8.9 nm) and chloroquine (EC 9.8 nm). Trimer 4 stood out as the most active agent against HCMV in vitro replication and exerted an EC value of 0.026 μm, representing an even higher activity than the two reference drugs ganciclovir (EC 2.60 μm) and artesunic acid (EC 5.41 μm). In addition, artemisinin-derived dimer 13 and trimer 15 were for the first time both immobilized on TOYOPEARL AF-Amino-650M beads and used for mass spectrometry-based target identification experiments using total lysates of HCMV-infected primary human fibroblasts. Two major groups of novel target candidates, namely cytoskeletal and mitochondrial proteins were obtained. Two putatively compound-binding viral proteins, namely major capsid protein (MCP) and envelope glycoprotein pUL132, which are both essential for HCMV replication, were identified.

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Section: Resultsmentioning

confidence: 72%

“…[b] EC 50 values have been previously reported . [c] EC 50 value has been previously reported . [d] EC 50 value has been previously reported .…”

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

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Synthesis of Artemisinin‐Derived Dimers, Trimers and Dendrimers: Investigation of Their Antimalarial and Antiviral Activities Including Putative Mechanisms of Action

Fröhlich

Hahn

Belmudes

et al. 2018

Chemistry A European J

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“…Since AS is known to interfere with the canonical NF-κB pathway by targeting RelA/p65 [28], we next determined whether AS treatment alone or in combination with Bic abrogates NF-κB signaling by performing NF-κB reporter assay in PC3 cells. As anticipated, a marked reduction in the NF-κB reporter activity was observed upon AS treatment alone or in combination with Bic (Figure 2 C ; P = 0.01 for both).…”

Section: Resultsmentioning

confidence: 99%

Targeting NF-kappa B Signaling by Artesunate Restores Sensitivity of Castrate-Resistant Prostate Cancer Cells to Antiandrogens

et al. 2017

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Androgen deprivation therapy (ADT) is the most preferred treatment for men with metastatic prostate cancer (PCa). However, the disease eventually progresses and develops resistance to ADT in majority of the patients, leading to the emergence of metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed artesunate (AS), an artemisinin derivative, for its anticancer properties and ability to alleviate resistance to androgen receptor (AR) antagonists. We have shown AS in combination with bicalutamide (Bic) attenuates the oncogenic properties of the castrate-resistant (PC3, 22RV1) and androgen-responsive (LNCaP) PCa cells. Mechanistically, AS and Bic combination inhibits nuclear factor (NF)-κB signaling and decreases AR and/or AR-variant 7 expression via ubiquitin-mediated proteasomal degradation. The combination induces oxidative stress and apoptosis via survivin downregulation and caspase-3 activation, resulting in poly-ADP-ribose polymerase (PARP) cleavage. Moreover, preclinical castrate-resistant PC3 xenograft studies in NOD/SCID mice (n =28, seven per group) show remarkable tumor regression and significant reduction in lungs and bone metastases upon administering AS (50 mg/kg per day in two divided doses) and Bic (50 mg/kg per day) via oral gavage. Taken together, we for the first time provide a compelling preclinical rationale that AS could disrupt AR antagonist–mediated resistance observed in mCRPC. The current study also indicates that the therapeutic combination of Food and Drug Administration–approved AS or NF-κB inhibitors and AR antagonists may enhance the clinical efficacy in the treatment of mCRPC patients.

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“…An HCMV GFP‐based replication assay was performed over a duration of seven days (multi‐round infection) using primary human foreskin fibroblasts (HFFs) infected with a GFP‐expressing recombinant human cytomegalovirus (HCMV AD169‐GFP) as described previously . All data represent mean values of determinations in quadruplicate [HCMV infections performed in duplicate, GFP measurements of total cell lysates performed in duplicate using automated quantitative GFP fluorometry in a Victor 1420 Multilabel Counter (PerkinElmer Wallac GmbH, Freiburg, Germany), as described] . Processing and evaluation of data was performed by the use of Excel (means and standard deviations).…”

Section: Methodsmentioning

confidence: 99%

Deeper Insight into the Six‐Step Domino Reaction of Aldehydes with Malononitrile and Evaluation of Antiviral and Antimalarial Activities of the Obtained Bicyclic Products

et al. 2017

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The straightforward and efficient synthesis of complex aza‐ and carbobicyclic compounds, which are of importance for medicinal chemistry, is a challenge for modern chemical methodology. An unprecedented metal‐free six‐step domino reaction of aldehydes with malononitrile was presented in our previous study to provide, in a single operation, these bicyclic nitrogen‐containing molecules. Presented here is a deeper investigation of this atom‐economical domino process by extending the scope of aldehydes, performing post‐modifications of domino products, applying bifunctional organocatalysts and comprehensive NMR studies of selected domino products. The thermodynamic aspects of the overall reaction are also demonstrated using DFT methods in conjunction with a semi‐empirical treatment of van der Waals interactions. Furthermore, biological studies of seven highly functionalized and artemisinin‐containing domino products against human cytomegalovirus (HCMV) and Plasmodium falciparum 3D7 are presented. Remarkably, in vitro tests against HCMV revealed five domino products to be highly active compounds (EC50 0.071–1.8 μm), outperforming the clinical reference drug ganciclovir (EC50 2.6 μm). Against P. falciparum 3D7, three of the investigated artemisinin‐derived domino products (EC50 0.72–1.8 nm) were more potent than the clinical drug chloroquine (EC50 9.1 nm).

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The broad-spectrum antiinfective drug artesunate interferes with the canonical nuclear factor kappa B (NF-κB) pathway by targeting RelA/p65

Cited by 49 publications

References 44 publications

Synthesis of Artemisinin‐Derived Dimers, Trimers and Dendrimers: Investigation of Their Antimalarial and Antiviral Activities Including Putative Mechanisms of Action

Synthesis of Artemisinin‐Derived Dimers, Trimers and Dendrimers: Investigation of Their Antimalarial and Antiviral Activities Including Putative Mechanisms of Action

Targeting NF-kappa B Signaling by Artesunate Restores Sensitivity of Castrate-Resistant Prostate Cancer Cells to Antiandrogens

Deeper Insight into the Six‐Step Domino Reaction of Aldehydes with Malononitrile and Evaluation of Antiviral and Antimalarial Activities of the Obtained Bicyclic Products

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