7 results on '"Shimozono R"'
Search Results
2. Discovery of anti-cell migration activity of an anti-HIV heterocyclic compound by identification of its binding protein hnRNP M.
- Author
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Kamo M, Ito M, Toma T, Gotoh H, Shimozono R, Nakagawa R, Koga R, Monde K, Tateishi H, Misumi S, Otsuka M, and Fujita M
- Subjects
- Anti-HIV Agents metabolism, Anti-HIV Agents pharmacology, Cell Line, Cell Movement drug effects, Down-Regulation drug effects, Drug Evaluation, Preclinical, Heterocyclic Compounds metabolism, Heterocyclic Compounds pharmacology, Heterogeneous-Nuclear Ribonucleoprotein Group M antagonists & inhibitors, Heterogeneous-Nuclear Ribonucleoprotein Group M genetics, Humans, Hyaluronan Receptors genetics, Hyaluronan Receptors metabolism, Protein Binding, Pyrimidines chemistry, Pyrimidines metabolism, Pyrimidines pharmacology, RNA Interference, RNA, Small Interfering chemistry, RNA, Small Interfering metabolism, Anti-HIV Agents chemistry, Heterocyclic Compounds chemistry, Heterogeneous-Nuclear Ribonucleoprotein Group M metabolism
- Abstract
One compound sometimes shows two biological functions, becoming important aspect of recent drug discovery. This study began with an attempt to confirm the previously reported molecular mechanism of the anti-human immunodeficiency virus (HIV) heterocyclic compound BMMP [2-(benzothiazol-2-ylmethylthio)-4-methylpyrimidine], i.e., induction of abnormal uncoating of the viral core at the post-entry step. Our mechanistic study gave results consistent with this mechanism. We further attempted to find out the molecular target of BMMP by a pulldown approach using previously synthesized biotinylated BMMP (Biotin-BMMP) and successfully identified heterogenous nuclear ribonucleoprotein M (hnRNP M) as a BMMP-binding protein. This protein was found not to be accountable for the anti-HIV activity of BMMP. As hnRNP M has been reported to promote cancer metastasis, we tested this mechanism and found that BMMP suppressed migration of the human lung carcinoma cell line A549 stimulated with transforming growth factor-β (TGF-β). Mechanistic study showed that BMMP suppressed the expression of CD44 mRNA via the regulation of hnRNP M. Furthermore, six new derivatives of BMMP were synthesized, and the patterns of their activities against HIV-1 and cell migration were not uniform, suggesting that the anti-HIV mechanism and the anti-cell migration mechanism of BMMP are independent. Taken together, the anti-cell migration activity of the anti-HIV heterocyclic compound BMMP was newly discovered by identification of its binding protein hnRNP M using a chemical biology approach., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
3. Development of a Novel Site-Specific Pegylated Interferon Beta for Antiviral Therapy of Chronic Hepatitis B Virus.
- Author
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Tsuge M, Uchida T, Hiraga N, Kan H, Makokha GN, Abe-Chayama H, Miki D, Imamura M, Ochi H, Hayes CN, Shimozono R, Iwamura T, Narumi H, Suzuki T, Kainoh M, Taniguchi T, and Chayama K
- Subjects
- Animals, Cell Line, Tumor, Chemokine CXCL10 biosynthesis, DNA, Circular metabolism, DNA, Viral metabolism, Hep G2 Cells, Humans, Mice, Mice, SCID, Mice, Transgenic, Recombinant Proteins pharmacology, Treatment Outcome, Viral Load drug effects, Virus Replication drug effects, Antiviral Agents pharmacology, Hepatitis B Surface Antigens metabolism, Hepatitis B virus drug effects, Hepatitis B, Chronic drug therapy, Interferon-alpha pharmacology, Polyethylene Glycols pharmacology
- Abstract
Although nucleot(s)ide analogues and pegylated interferon alpha 2a (PEG-IFN-α2a) can suppress hepatitis B virus (HBV) replication, it is difficult to achieve complete HBV elimination from hepatocytes. A novel site-specific pegylated recombinant human IFN-β (TRK-560) was recently developed. In the present study, we evaluated the antiviral effects of TRK-560 on HBV replication in vitro and in vivo. In vitro and in vivo HBV replication models were treated with antivirals including TRK-560, and changes in HBV markers were evaluated. To analyze antiviral mechanisms, cDNA microarray analysis and an enzyme-linked immunoassay (ELISA) were performed. TRK-560 significantly suppressed the production of intracellular HBV replication intermediates and extracellular HBV surface antigen (HBsAg) ( P < 0.001 and P < 0.001, respectively), and the antiviral effects of TRK-560 were enhanced in combination with nucleot(s)ide analogues, such as entecavir and tenofovir disoproxil fumarate. The reduction in HBV DNA levels by TRK-560 treatment was significantly higher than that by PEG-IFN-α2a treatment both in vitro and in vivo ( P = 0.004 and P = 0.046, respectively), and intracellular HBV covalently closed circular DNA (cccDNA) reduction by TRK-560 treatment was also significantly higher than that by PEG-IFN-α2a treatment in vivo ( P = 0.0495). cDNA microarrays and ELISA for CXCL10 production revealed significant differences between TRK-560 and PEG-IFN-α2a in the induction potency of interferon-stimulated genes. TRK-560 shows a stronger antiviral potency via higher induction of interferon-stimulated genes and stronger stimulation of immune cell chemotaxis than PEG-IFN-α2a. As HBsAg loss and HBV cccDNA eradication are important clinical goals, these results suggest a potential role for TRK-560 in the development of more effective treatment for chronic hepatitis B infection., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
- Full Text
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4. Discovery of Peripheral κ-Opioid Receptor Agonists as Novel Analgesics.
- Author
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Suzuki S, Sugawara Y, Inada H, Tsuji R, Inoue A, Tanimura R, Shimozono R, Konno M, Ohyama T, Higashi E, Sakai C, and Kawai K
- Subjects
- Acetic Acid, Analgesics chemical synthesis, Analgesics chemistry, Animals, Dose-Response Relationship, Drug, Male, Mice, Mice, Inbred ICR, Models, Molecular, Molecular Conformation, Morphinans chemical synthesis, Morphinans chemistry, Pain chemically induced, Spiro Compounds chemical synthesis, Spiro Compounds chemistry, Structure-Activity Relationship, Analgesics pharmacology, Drug Discovery, Morphinans pharmacology, Pain drug therapy, Receptors, Opioid, kappa agonists, Spiro Compounds pharmacology
- Abstract
κ-Opioid receptor agonists with high selectivity over the μ-opioid receptor and peripheral selectivity are attractive targets in the development of drugs for pain. We have previously attempted to create novel analgesics with peripheral selective κ-opioid receptor agonist on the basis of TRK-820. In this study, we elucidated the biological properties of 17-hydroxy-cyclopropylmethyl and 10α-hydroxy derivatives. These compounds were found to have better κ-opioid receptor selectivity and peripheral selectivity than TRK-820.
- Published
- 2017
- Full Text
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5. Multiple binding modes of a small molecule to human Keap1 revealed by X-ray crystallography and molecular dynamics simulation.
- Author
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Satoh M, Saburi H, Tanaka T, Matsuura Y, Naitow H, Shimozono R, Yamamoto N, Inoue H, Nakamura N, Yoshizawa Y, Aoki T, Tanimura R, and Kunishima N
- Abstract
Keap1 protein acts as a cellular sensor for oxidative stresses and regulates the transcription level of antioxidant genes through the ubiquitination of a corresponding transcription factor, Nrf2. A small molecule capable of binding to the Nrf2 interaction site of Keap1 could be a useful medicine. Here, we report two crystal structures, referred to as the soaking and the cocrystallization forms, of the Kelch domain of Keap1 with a small molecule, Ligand1. In these two forms, the Ligand1 molecule occupied the binding site of Keap1 so as to mimic the ETGE motif of Nrf2, although the mode of binding differed in the two forms. Because the Ligand1 molecule mediated the crystal packing in both the forms, the influence of crystal packing on the ligand binding was examined using a molecular dynamics (MD) simulation in aqueous conditions. In the MD structures from the soaking form, the ligand remained bound to Keap1 for over 20 ns, whereas the ligand tended to dissociate in the cocrystallization form. The MD structures could be classified into a few clusters that were related to but distinct from the crystal structures, indicating that the binding modes observed in crystals might be atypical of those in solution. However, the dominant ligand recognition residues in the crystal structures were commonly used in the MD structures to anchor the ligand. Therefore, the present structural information together with the MD simulation will be a useful basis for pharmaceutical drug development.
- Published
- 2015
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6. Orally-administered caspase inhibitor PF-03491390 is retained in the liver for prolonged periods with low systemic exposure, exerting a hepatoprotective effect against alpha-fas-induced liver injury in a mouse model.
- Author
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Ueno Y, Ohmi T, Yamamoto M, Kato N, Moriguchi Y, Kojima M, Shimozono R, Suzuki S, Matsuura T, and Eda H
- Subjects
- Administration, Oral, Alanine Transaminase blood, Alanine Transaminase drug effects, Animals, Antibodies, Monoclonal toxicity, Antibodies, Monoclonal, Murine-Derived, Apoptosis drug effects, Chemical and Drug Induced Liver Injury, Disease Models, Animal, Drug Administration Schedule, Drug Delivery Systems, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors pharmacokinetics, Liver metabolism, Male, Mice, Mice, Inbred BALB C, Pentanoic Acids administration & dosage, Pentanoic Acids pharmacokinetics, Tissue Distribution, Caspase Inhibitors, Enzyme Inhibitors pharmacology, Liver Diseases drug therapy, Pentanoic Acids pharmacology
- Abstract
In a mouse model of alpha-Fas-induced acute liver injury, the orally-administered caspase inhibitor PF-03491390 (formerly named IDN-6556) was retained in the liver for prolonged periods with a low systemic exposure. Reductions in the elevated plasma levels of alanine aminotransferase (ALT) revealed that the retention of PF-03491390 in the liver exerted a hepatoprotective effect, even when pre-administered to mice 4 h before alpha-Fas insult. Prolonged retention of PF-03491390 in the liver after oral administration has the benefit of low systemic exposure, making this a beneficial agent for the treatment of liver diseases.
- Published
- 2007
- Full Text
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7. Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1.
- Author
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Takeda K, Shimozono R, Noguchi T, Umeda T, Morimoto Y, Naguro I, Tobiume K, Saitoh M, Matsuzawa A, and Ichijo H
- Subjects
- Amino Acid Sequence, Animals, Carrier Proteins analysis, Cells, Cultured, Humans, MAP Kinase Kinase Kinase 5 metabolism, MAP Kinase Kinase Kinases chemistry, Mice, Molecular Sequence Data, Oxidative Stress, Phosphorylation, MAP Kinase Kinase Kinase 5 chemistry, MAP Kinase Kinase Kinases physiology
- Abstract
Apoptosis signal-regulating kinase (ASK) 1 is a mitogen-activated protein kinase kinase kinase (MAP3K) in the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase pathways that play multiple important roles in cytokine and stress responses. Here we show that ASK2, a highly related serine/threonine kinase to ASK1, also functions as a MAP3K only in a heteromeric complex with ASK1. We found that endogenous ASK2 was constitutively degraded in ASK1-deficient cells, suggesting that ASK1 is required for the stability of ASK2. ASK2 in a heteromeric complex with a kinase-negative mutant of ASK1 (ASK1-KN) effectively activated MAP2K and was more competent to respond to oxidative stress than ASK2 alone. Knockdown of ASK2 revealed that ASK2 was required for oxidative stress-induced JNK activation. These results suggest that ASK2 forms a functional MAP3K complex with ASK1, in which ASK1 supports the stability and the active configuration of ASK2. Moreover, ASK2 was found to activate ASK1 by direct phosphorylation, suggesting that ASK1 and ASK2 in a heteromeric complex facilitate their activities to each other by distinct mechanisms. Such a formation of functional heteromeric complex between different MAP3Ks may be advantageous for cells to cope with a wide variety of stimuli by fine regulation of cellular responses.
- Published
- 2007
- Full Text
- View/download PDF
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