Introduction of New Tools for Chemical Biology Research on Microbial Metabolites

Osada, Hiroyuki

doi:10.1271/bbb.100061

Cited by 45 publications

(31 citation statements)

References 20 publications

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“…screen 29,809 compounds from a chemical library of the RIKEN Natural Products Depository (NPDepo) 32,33 . Twenty MTH1 binders were detected (Fig.…”

Section: Identification Of New Mth1 Inhibitors To Identify New Mth1 mentioning

confidence: 99%

Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival

Kawamura¹,

Kawatani²,

Muroi³

et al. 2016

European Journal of Cancer

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“…screen 29,809 compounds from a chemical library of the RIKEN Natural Products Depository (NPDepo) 32,33 . Twenty MTH1 binders were detected (Fig.…”

Section: Identification Of New Mth1 Inhibitors To Identify New Mth1 mentioning

confidence: 99%

Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival

Kawamura¹,

Kawatani²,

Muroi³

et al. 2016

European Journal of Cancer

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“…N atural products possess a wide range of structural and functional diversity, with many of them exhibiting drug-like properties (1)(2)(3)(4). Thus, natural products have been a rich source of new drugs for treating many diseases, while also serving as probes for characterizing molecules and pathways critical for biological processes.…”

mentioning

confidence: 99%

Fungus-Derived Neoechinulin B as a Novel Antagonist of Liver X Receptor, Identified by Chemical Genetics Using a Hepatitis C Virus Cell Culture System

Nakajima

Watashi

Ohashi

et al. 2016

J Virol

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Cell culture systems reproducing virus replication can serve as unique models for the discovery of novel bioactive molecules. Here, using a hepatitis C virus (HCV) cell culture system, we identified neoechinulin B (NeoB), a fungus-derived compound, as an inhibitor of the liver X receptor (LXR). NeoB was initially identified by chemical screening as a compound that impeded the production of infectious HCV. Genome-wide transcriptome analysis and reporter assays revealed that NeoB specifically inhibits LXR-mediated transcription. NeoB was also shown to interact directly with LXRs. Analysis of structural analogs suggested that the molecular interaction of NeoB with LXR correlated with the capacity to inactivate LXR-mediated transcription and to modulate lipid metabolism in hepatocytes. Our data strongly suggested that NeoB is a novel LXR antagonist. Analysis using NeoB as a bioprobe revealed that LXRs support HCV replication: LXR inactivation resulted in dispersion of double-membrane vesicles, putative viral replication sites. Indeed, cells treated with NeoB showed decreased replicative permissiveness for poliovirus, which also replicates in double-membrane vesicles, but not for dengue virus, which replicates via a distinct membrane compartment. Together, our data suggest that LXR-mediated transcription regulates the formation of virus-associated membrane compartments. Significantly, inhibition of LXRs by NeoB enhanced the activity of all known classes of anti-HCV agents, and NeoB showed especially strong synergy when combined with interferon or an HCV NS5A inhibitor. Thus, our chemical genetics analysis demonstrates the utility of the HCV cell culture system for identifying novel bioactive molecules and characterizing the virushost interaction machinery. IMPORTANCEHepatitis C virus (HCV) is highly dependent on host factors for efficient replication. In the present study, we used an HCV cell culture system to screen an uncharacterized chemical library. Our results identified neoechinulin B (NeoB) as a novel inhibitor of the liver X receptor (LXR). NeoB inhibited the induction of LXR-regulated genes and altered lipid metabolism. Intriguingly, our results indicated that LXRs are critical to the process of HCV replication: LXR inactivation by NeoB disrupted double-membrane vesicles, putative sites of viral replication. Moreover, NeoB augmented the antiviral activity of all known classes of currently approved anti-HCV agents without increasing cytotoxicity. Thus, our strategy directly links the identification of novel bioactive compounds to basic virology and the development of new antiviral agents.

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“…Dp44mT, deferoxamine mesylate salt, ammonium tetrathiomolybdate (TM), and N,N,N′,N′-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) were purchased from Sigma-Aldrich. Antimycin A was obtained from the RIKEN Natural Products Depository (NPDepo)40.…”

Section: Methodsmentioning

confidence: 99%

Proteomic profiling reveals that collismycin A is an iron chelator

Kawatani

Muroi

Wada³

et al. 2016

Sci Rep

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Collismycin A (CMA), a microbial product, has anti-proliferative activity against cancer cells, but the mechanism of its action remains unknown. Here, we report the identification of the molecular target of CMA by ChemProteoBase, a proteome-based approach for drug target identification. ChemProteoBase profiling showed that CMA is closely clustered with di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, an iron chelator. CMA bound to both Fe(II) and Fe(III) ions and formed a 2:1 chelator-iron complex with a redox-inactive center. CMA-induced cell growth inhibition was completely canceled by Fe(II) and Fe(III) ions, but not by other metal ions such as Zn(II) or Cu(II). Proteomic and transcriptomic analyses showed that CMA affects the glycolytic pathway due to the accumulation of HIF-1α. These results suggest that CMA acts as a specific iron chelator, leading to the inhibition of cancer cell growth.

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Introduction of New Tools for Chemical Biology Research on Microbial Metabolites

Cited by 45 publications

References 20 publications

Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival

Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival

Fungus-Derived Neoechinulin B as a Novel Antagonist of Liver X Receptor, Identified by Chemical Genetics Using a Hepatitis C Virus Cell Culture System

Proteomic profiling reveals that collismycin A is an iron chelator

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