EM2487, a Novel Anti-HIV-1 Antibiotic, Produced by Streptomyces sp. Mer-2487. Taxonomy, Fermentation, Biological Properties, Isolation and Structure Elucidation.

Takeuchi, Hitoshi; Asai, Naoki; Tanabe, Kazunori; Kozaki, Teruya; Fujita, Masanori; Sakai, Takashi; Okuda, Akifumi; Naruse, Nobuaki; Yamamoto, Satoshi; Sameshima, Tomohiro; Heida, Naohiko; Dobashi, Kazuyuki; Baba, Masanori

doi:10.7164/antibiotics.52.971

Cited by 16 publications

(11 citation statements)

References 16 publications

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“…The structure elucidation of K‐563 revealed that this natural product was uniquely composed of alkylamine, phosphate imide of glycinamide, oxygenated cyclopentane, and nucleoside units. This composition has also been observed in 1100‐50 and EM2487, making K‐563 the third compound in this natural product category. In the context of their activity, 1100‐50 and EM2487 have been reported as a nematocide and an anti‐human immunodeficiency virus (HIV) compound, respectively.…”

Section: Discussionsupporting

confidence: 60%

“…This composition has also been observed in 1100‐50 and EM2487, making K‐563 the third compound in this natural product category. In the context of their activity, 1100‐50 and EM2487 have been reported as a nematocide and an anti‐human immunodeficiency virus (HIV) compound, respectively. In this study, we showed for the first time that K‐563 exerted Keap1/Nrf2 pathway inhibition and potent anti‐proliferative effects against cancer cells.…”

Section: Discussionsupporting

confidence: 60%

“…Based on LC‐MS analysis of the isolated K‐563, the UV λmax 273.4 nm (Figure C) and the molecular weight 828 (Figure D) were observed. This indicated that K‐563 was an analogue compound of 1100‐50 and EM2487 according to a database, Dictionary of Natural Products Version 22:1 (CRC press). The structure of K‐563 was finally elucidated by spectroscopic data analyses described below.…”

Section: Resultsmentioning

confidence: 99%

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The discovery and characterization of K‐563, a novel inhibitor of the Keap1/Nrf2 pathway produced by Streptomyces sp

et al. 2019

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Keap1/Nrf2 pathway regulates the antioxidant stress response, detoxification response, and energy metabolism. Previous reports found that aberrant Keap1/Nrf2 pathway activation due to Kelch‐like ECH‐associated protein 1 (Keap1) mutations or Nuclear factor E2‐related factor 2 (Nrf2) mutations induced resistance of cancer cells to chemotherapy and accelerated cell growth via the supply of nutrients. Therefore, Keap1/Nrf2 pathway activation is associated with a poor prognosis in many cancers. These previous findings suggested that inhibition of Keap1/Nrf2 pathway could be a target for anti‐cancer therapies. To discover a small‐molecule Keap1/Nrf2 pathway inhibitor, we conducted high‐throughput screening in Keap1 mutant human lung cancer A549 cells using a transcriptional reporter assay. Through this screening, we identified the novel Keap1/Nrf2 pathway inhibitor K‐563, which was isolated from actinomycete Streptomyces sp. K‐563 suppressed the expression of Keap1/Nrf2 pathway downstream target genes or the downstream target protein, which induced suppression of GSH production, and activated reactive oxygen species production in A549 cells. K‐563 also inhibited the expression of downstream target genes in other Keap1‐ or Nrf2‐mutated cancer cells. Furthermore, K‐563 exerted anti‐proliferative activities in these mutated cancer cells. These in vitro analyses showed that K‐563 was able to inhibit cell growth in Keap1‐ or Nrf2‐mutated cancer cells by Keap1/Nrf2 pathway inhibition. K‐563 also exerted synergistic combinational effects with lung cancer chemotherapeutic agents. An in vivo study in mice xenotransplanted with A549 cells to further explore the therapeutic potential of K‐563 revealed that it also inhibited Keap1/Nrf2 pathway in lung cancer tumors. K‐563, a novel Keap1/Nrf2 pathway inhibitor, may be a lead compound for development as an anti‐cancer agent.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionsupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

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The discovery and characterization of K‐563, a novel inhibitor of the Keap1/Nrf2 pathway produced by Streptomyces sp

et al. 2019

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“…Thus, targeting the Tat basic domain may provide a new rationale for designing antivirals [13,15,170]. Different classes of compounds were found to inhibit HIV-1 replication due to (at least in part) interferences with Tat: fluoroquinolones of types 115 (K-12) and 116 (K37) [171,172]; the natural product EM2487 117, isolated from a Streptomyces strain [173]; the bis-triazoloacridone tamacrazine 118 [174], or the peptoid incorporating highly basic residues CGP 64222 119 [175]; the 19-residue cyclopeptide 120 [176], or the stilbene sulfonate derivative CGA 137053 121 [177] among others.…”

Section: Compounds Interacting With Tat/tarmentioning

confidence: 99%

Highly Active Antiretroviral Therapy: Current State of the Art, New Agents and Their Pharmacological Interactions Useful for Improving Therapeutic Outcome

Bárbaro

Scozzafava²,

Mastrolorenzo³

et al. 2005

CPD

212

148

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Highly active antiretroviral therapy (HAART) dramatically changed the course of HIV infection. Currently, this therapy involves the use of agents from at least two distinct classes of antivirals: a protease inhibitor (PI) in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with NRTIs. Recently, the third family of antivirals started to be used clinically, with the advent of enfuvirtide, the first fusion inhibitor (FI). Several pharmacological agents are available form these classes of antivirals, NRTIs, NNRTIs, PIs and FIs, which will be briefly reviewed here. Some more agents are in advanced clinical evaluation or have recently been approved (such as tenofovir, a NtRTI; atazanavir, a PI; tipranavir, another PI), mainly against drug-resistant viruses. Compounds inhibiting HIV integrase, the third enzyme of HIV, are also available ultimately, with several such derivatives in clinical trials (L-731, 988 and S-1360). Another approach to inhibit the growth of retroviruses, including HIV, targets the ejection of zinc ions from critical zinc finger viral proteins, which has as a consequence the inhibition of viral replication in the absence of mutations leading to drug resistance phenotypes. All steps in the process of HIV entry into the cell may be targeted by specific compounds that might be developed as novel types of antiretrovirals. Thus, inhibitors of the gp120-CD4 interaction have been detected (zintevir, FP-21399 and BMS-378806 in clinical trials). Small molecule chemokine antagonists acting as HIV entry inhibitors also were described in the last period, which interact both with the CXCR4 coreceptor (such as AMD3100; AMD3465; ALX40-4C; T22, T134 and T140), or which are antagonist of the CCR5 coreceptor (TAK-779, TAK-220, SCH-C, SCH-D, E913, AK-602 and NSC 651016 in clinical trials), together with new types of fusion inhibitors possessing the same mechanism of action as enfuvirtide (such as T1249). Compounds interacting with Tat/Tar have also been detected which inhibit HIV replication in low micromolar range (EM2487, tamacrazine, CGP 64222 or CGA 137053 among others). Unexploited viral and cellular targets (such as the maturation process-with a first potent compound available, PA-457; the cellular proteins Tsg101, APOBEC3G, or the viral ones Vif, Rev or RNase H) are also presented, together with recently emerged approaches for eradication of HIV reservoirs. A review on the pharmacology and interactions of these agents with other drugs is presented here, with emphasis on how these pharmacological interferences may improve the clinical use of antivirals, or how side effects due to these drugs may be managed better by taking them into account.

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“…Mer-2487 though a program to discover a novel compound that inhibits HIV-1 transcription using human T cell lines that are able to produce a secretory form of alkaline phosphatase under the control of HIV-1 long-terminal repeat [51]. EM2487 is the first representative of a new class of nucleoside natural products whose chemical structure is very unique.…”

Section: Em2487 and 1100-50mentioning

confidence: 99%

Nucleoside natural products and related analogs with potential therapeutic properties as antibacterial and antiviral agents

Ichikawa¹,

Matsuda²

2007

Expert Opinion on Therapeutic Patents

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Nucleoside natural products possess a variety of interesting biological activities, including antibacterial, antiviral and antitumor properties, and are therefore expected to be potential candidates for developing drugs. Complex nucleoside natural products exhibiting antibacterial activity by specific inhibition of bacterial cell wall peptidoglycan biosynthesis are described. In addition to the class of antibacterial nucleoside natural products, the newest members of nucleoside natural products exhibiting interesting antiviral activity are briefly described. In spite of promising properties, no nucleoside natural products and their analogs are presently used in the clinic. A global structure-activity relationship of these classes of nucleoside natural products clearly indicates that it is very important to: i) modulate the cell entry ability; and ii) simplify hydrophilic core structures in order to reduce the size of molecules and stabilize the chemically labile structure.

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EM2487, a Novel Anti-HIV-1 Antibiotic, Produced by Streptomyces sp. Mer-2487. Taxonomy, Fermentation, Biological Properties, Isolation and Structure Elucidation.

Abstract: For the purpose of discovering novel agents that inhibit HIV-1 replication at the transcriptional level, we have established cell lines reflecting the HIV-1 long terminal repeatdriven gene expression. Using these cell lines, we have screened approximately 10,000

Cited by 16 publications

References 16 publications

The discovery and characterization of K‐563, a novel inhibitor of the Keap1/Nrf2 pathway produced by Streptomyces sp

The discovery and characterization of K‐563, a novel inhibitor of the Keap1/Nrf2 pathway produced by Streptomyces sp

Highly Active Antiretroviral Therapy: Current State of the Art, New Agents and Their Pharmacological Interactions Useful for Improving Therapeutic Outcome

Nucleoside natural products and related analogs with potential therapeutic properties as antibacterial and antiviral agents

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