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Wieland B. Huttner - One of the best experts on this subject based on the ideXlab platform.
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Cooperativity of phosphatidylinositol transfer protein and phospholipase D in secretory vesicle formation from the TGN – phosphoinositides as a common denominator?
FEBS Letters, 1997Co-Authors: Oliver Tüscher, Christoph Lorra, Barend Bouma, Karel W. A. Wirtz, Wieland B. HuttnerAbstract:Phosphatidylinositol transfer protein (PITP) and phospholipase D (PLD) stimulate the formation of constitutive secretory vesicles (CSVs) and immature secretory granules (ISGs) from the trans-Golgi network (TGN) in a cell-free system. The stimulatory effects of PITP and PLD are additive. Stimulation by either PITP or PLD is blocked by Geneticin, a member of the aminoglycoside antibiotics known to bind to phosphoinositides. Since the PLD we used is insensitive to Geneticin, our results suggest that phosphoinositides promote secretory vesicle formation as downstream effectors of both PITP and PLD, possibly via the recruitment of proteins mediating membrane budding and fission.
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Cooperativity of phosphatidylinositol transfer protein and phospholipase D in secretory vesicle formation from the TGN--phosphoinositides as a common denominator?
FEBS letters, 1997Co-Authors: Oliver Tüscher, Christoph Lorra, Barend Bouma, Karel W. A. Wirtz, Wieland B. HuttnerAbstract:Phosphatidylinositol transfer protein (PITP) and phospholipase D (PLD) stimulate the formation of constitutive secretory vesicles (CSVs) and immature secretory granules (ISGs) from the trans-Golgi network (TGN) in a cell-free system. The stimulatory effects of PITP and PLD are additive. Stimulation by either PITP or PLD is blocked by Geneticin, a member of the aminoglycoside antibiotics known to bind to phosphoinositides. Since the PLD we used is insensitive to Geneticin, our results suggest that phosphoinositides promote secretory vesicle formation as downstream effectors of both PITP and PLD, possibly via the recruitment of proteins mediating membrane budding and fission.
Oliver Tüscher - One of the best experts on this subject based on the ideXlab platform.
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Cooperativity of phosphatidylinositol transfer protein and phospholipase D in secretory vesicle formation from the TGN – phosphoinositides as a common denominator?
FEBS Letters, 1997Co-Authors: Oliver Tüscher, Christoph Lorra, Barend Bouma, Karel W. A. Wirtz, Wieland B. HuttnerAbstract:Phosphatidylinositol transfer protein (PITP) and phospholipase D (PLD) stimulate the formation of constitutive secretory vesicles (CSVs) and immature secretory granules (ISGs) from the trans-Golgi network (TGN) in a cell-free system. The stimulatory effects of PITP and PLD are additive. Stimulation by either PITP or PLD is blocked by Geneticin, a member of the aminoglycoside antibiotics known to bind to phosphoinositides. Since the PLD we used is insensitive to Geneticin, our results suggest that phosphoinositides promote secretory vesicle formation as downstream effectors of both PITP and PLD, possibly via the recruitment of proteins mediating membrane budding and fission.
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Cooperativity of phosphatidylinositol transfer protein and phospholipase D in secretory vesicle formation from the TGN--phosphoinositides as a common denominator?
FEBS letters, 1997Co-Authors: Oliver Tüscher, Christoph Lorra, Barend Bouma, Karel W. A. Wirtz, Wieland B. HuttnerAbstract:Phosphatidylinositol transfer protein (PITP) and phospholipase D (PLD) stimulate the formation of constitutive secretory vesicles (CSVs) and immature secretory granules (ISGs) from the trans-Golgi network (TGN) in a cell-free system. The stimulatory effects of PITP and PLD are additive. Stimulation by either PITP or PLD is blocked by Geneticin, a member of the aminoglycoside antibiotics known to bind to phosphoinositides. Since the PLD we used is insensitive to Geneticin, our results suggest that phosphoinositides promote secretory vesicle formation as downstream effectors of both PITP and PLD, possibly via the recruitment of proteins mediating membrane budding and fission.
Alex V. Birk - One of the best experts on this subject based on the ideXlab platform.
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Geneticin stabilizes the open conformation of the 5 region of hepatitis c virus rna and inhibits viral replication
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Ascension Arizamateos, Timothy M. Block, Alex V. Birk, Rosa Diaztoledano, Samuel Prietovega, Jordi GómezAbstract:The aminoglycoside Geneticin (G418) is known to inhibit cell culture proliferation, via virus-specific mechanisms, of two different virus genera from the family Flaviviridae. Here, we tried to determine whether Geneticin can selectively alter the switching of the nucleotide 1 to 570 RNA region of hepatitis C virus (HCV) and, if so, whether this inhibits viral growth. Two structure-dependent RNases known to specifically cleave HCV RNA were tested in the presence or absence of the drug. One was the Synechocystis sp. RNase P ribozyme, which cleaves the tRNA-like domain around the AUG start codon under high-salt buffer conditions; the second was Escherichia coli RNase III, which recognizes a double-helical RNA switch element that changes the internal ribosome entry site (IRES) from a closed (C) conformation to an open (O) one. While the drug did not affect RNase P activity, it did inhibit RNase III in the micromolar range. Kinetic studies indicated that the drug favors the switch from the C to the O conformation of the IRES by stabilizing the distal double-stranded element and inhibiting further processing of the O form. We demonstrate that, because the RNA in this region is highly conserved and essential for virus survival, Geneticin inhibits HCV Jc1 NS3 expression, the release of the viral genomic RNA, and the propagation of HCV in Huh 7.5 cells. Our study highlights the crucial role of riboswitches in HCV replication and suggests the therapeutic potential of viral-RNA-targeted antivirals.
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Geneticin Stabilizes the Open Conformation of the 5′ Region of Hepatitis C Virus RNA and Inhibits Viral Replication
Antimicrobial agents and chemotherapy, 2015Co-Authors: Ascensión Ariza-mateos, Timothy M. Block, Alex V. Birk, Rosa Diaz-toledano, Samuel Prieto-vega, Jordi GómezAbstract:The aminoglycoside Geneticin (G418) is known to inhibit cell culture proliferation, via virus-specific mechanisms, of two different virus genera from the family Flaviviridae. Here, we tried to determine whether Geneticin can selectively alter the switching of the nucleotide 1 to 570 RNA region of hepatitis C virus (HCV) and, if so, whether this inhibits viral growth. Two structure-dependent RNases known to specifically cleave HCV RNA were tested in the presence or absence of the drug. One was the Synechocystis sp. RNase P ribozyme, which cleaves the tRNA-like domain around the AUG start codon under high-salt buffer conditions; the second was Escherichia coli RNase III, which recognizes a double-helical RNA switch element that changes the internal ribosome entry site (IRES) from a closed (C) conformation to an open (O) one. While the drug did not affect RNase P activity, it did inhibit RNase III in the micromolar range. Kinetic studies indicated that the drug favors the switch from the C to the O conformation of the IRES by stabilizing the distal double-stranded element and inhibiting further processing of the O form. We demonstrate that, because the RNA in this region is highly conserved and essential for virus survival, Geneticin inhibits HCV Jc1 NS3 expression, the release of the viral genomic RNA, and the propagation of HCV in Huh 7.5 cells. Our study highlights the crucial role of riboswitches in HCV replication and suggests the therapeutic potential of viral-RNA-targeted antivirals.
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Antiviral activity of Geneticin against dengue virus.
Antiviral research, 2009Co-Authors: Xianchao G. Zhang, Peter W. Mason, Edward J. Dubovi, Nigel Bourne, Randall W. Renshaw, Timothy M. Block, Alex V. BirkAbstract:The aminoglycoside, Geneticin (G418), was recently shown to have antiviral activity against bovine viral diarrhea virus (BVDV). Since BVDV, dengue virus (DENV) and yellow fever virus (YFV) all belong to the Flaviviridae family, it seemed possible that a common step in their life cycle might be affected by this aminoglycoside. Here it is shown that Geneticin prevented the cytopathic effect (CPE) resulting from DENV-2 infection of BHK cells, in a dose-dependent manner with an 50% effective concentration (EC(50)) value of 3+/-0.4microg/ml. Geneticin had no detectable effect on CPE caused by YFV in BHK cells. Geneticin also inhibited DENV-2 viral yield with an EC(50) value of 2+/-0.1microg/ml and an EC(90) value of 20+/-2microg/ml. With a CC(50) value of 165+/-5microg/ml, the selectivity index of anti-DENV activity of Geneticin in BHK cells was established to be 66. Furthermore, 25microg/ml of Geneticin nearly completely blocked plaque formation induced by DENV-2, but not YFV. In addition, Geneticin, inhibited DENV-2 viral RNA replication and viral translation. Gentamicin, kanamycin, and the guanidinylated Geneticin showed no anti-DENV activity. Neomycin and paromomycin demonstrated weak antiviral activity at high concentrations. Finally, aminoglycoside-3'-phosphotransferase activity of neomycin-resistant gene abolished antiviral activity of Geneticin.
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Antiviral activity of Geneticin against bovine viral diarrhoea virus
Antiviral chemistry & chemotherapy, 2008Co-Authors: Alex V. Birk, Edward J. Dubovi, Xianchao Zhang, Hazel H. SzetoAbstract:Background: Aminoglycoside G418 is commonly used to generate stable replicons for RNA viruses, such as hepatitis C virus, West Nile virus, and bovine viral diarrhoea virus (BVDV). This precludes testing G418’s own antiviral activities against those viruses. Here, we report antiviral activity of G418 against BVDV. Methods: Cell viability and virus yield reduction assays were used to investigate antiviral effects of G418 against BVDV. The expression of viral proteins and RNA were determined by western blot and real-time quantitive PCR, respectively. Results: We demonstrated that G418 (50% cytotoxicity concentration of 400 µg/ml) improved cell viability of Madin–Darby bovine kidney cells infected with a cytopathic strain of BVDV (NADL) in a dose-dependent manner with 50% effective concentration of 4 µg/ml. Interestingly, close structural analogues with known properties as translation inhibitors similar to G418 – kanamycin and gentamicin – had no antiviral activity against BVDV. In addition, G418 inhibits virus yield of two different strains of BVDV (NADL and NY-1) without affecting viral RNA replication and translation or viral NS3 protein processing. Conclusion: Our data indicate that antiviral activity of G418 could result from interference with either the assembly or release of active virus, rather than the regulation of viral translation and replication. Thus, we propose the use of chemical analogues of G418 as antiviral therapeutics for treatment of viral diseases associated with the Flaviviridae family, such as hepatitis C virus, dengue virus, yellow fever virus, West Nile virus and others.
Jordi Gómez - One of the best experts on this subject based on the ideXlab platform.
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Geneticin stabilizes the open conformation of the 5 region of hepatitis c virus rna and inhibits viral replication
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Ascension Arizamateos, Timothy M. Block, Alex V. Birk, Rosa Diaztoledano, Samuel Prietovega, Jordi GómezAbstract:The aminoglycoside Geneticin (G418) is known to inhibit cell culture proliferation, via virus-specific mechanisms, of two different virus genera from the family Flaviviridae. Here, we tried to determine whether Geneticin can selectively alter the switching of the nucleotide 1 to 570 RNA region of hepatitis C virus (HCV) and, if so, whether this inhibits viral growth. Two structure-dependent RNases known to specifically cleave HCV RNA were tested in the presence or absence of the drug. One was the Synechocystis sp. RNase P ribozyme, which cleaves the tRNA-like domain around the AUG start codon under high-salt buffer conditions; the second was Escherichia coli RNase III, which recognizes a double-helical RNA switch element that changes the internal ribosome entry site (IRES) from a closed (C) conformation to an open (O) one. While the drug did not affect RNase P activity, it did inhibit RNase III in the micromolar range. Kinetic studies indicated that the drug favors the switch from the C to the O conformation of the IRES by stabilizing the distal double-stranded element and inhibiting further processing of the O form. We demonstrate that, because the RNA in this region is highly conserved and essential for virus survival, Geneticin inhibits HCV Jc1 NS3 expression, the release of the viral genomic RNA, and the propagation of HCV in Huh 7.5 cells. Our study highlights the crucial role of riboswitches in HCV replication and suggests the therapeutic potential of viral-RNA-targeted antivirals.
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Geneticin Stabilizes the Open Conformation of the 5′ Region of Hepatitis C Virus RNA and Inhibits Viral Replication
Antimicrobial agents and chemotherapy, 2015Co-Authors: Ascensión Ariza-mateos, Timothy M. Block, Alex V. Birk, Rosa Diaz-toledano, Samuel Prieto-vega, Jordi GómezAbstract:The aminoglycoside Geneticin (G418) is known to inhibit cell culture proliferation, via virus-specific mechanisms, of two different virus genera from the family Flaviviridae. Here, we tried to determine whether Geneticin can selectively alter the switching of the nucleotide 1 to 570 RNA region of hepatitis C virus (HCV) and, if so, whether this inhibits viral growth. Two structure-dependent RNases known to specifically cleave HCV RNA were tested in the presence or absence of the drug. One was the Synechocystis sp. RNase P ribozyme, which cleaves the tRNA-like domain around the AUG start codon under high-salt buffer conditions; the second was Escherichia coli RNase III, which recognizes a double-helical RNA switch element that changes the internal ribosome entry site (IRES) from a closed (C) conformation to an open (O) one. While the drug did not affect RNase P activity, it did inhibit RNase III in the micromolar range. Kinetic studies indicated that the drug favors the switch from the C to the O conformation of the IRES by stabilizing the distal double-stranded element and inhibiting further processing of the O form. We demonstrate that, because the RNA in this region is highly conserved and essential for virus survival, Geneticin inhibits HCV Jc1 NS3 expression, the release of the viral genomic RNA, and the propagation of HCV in Huh 7.5 cells. Our study highlights the crucial role of riboswitches in HCV replication and suggests the therapeutic potential of viral-RNA-targeted antivirals.
Karel W. A. Wirtz - One of the best experts on this subject based on the ideXlab platform.
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Cooperativity of phosphatidylinositol transfer protein and phospholipase D in secretory vesicle formation from the TGN – phosphoinositides as a common denominator?
FEBS Letters, 1997Co-Authors: Oliver Tüscher, Christoph Lorra, Barend Bouma, Karel W. A. Wirtz, Wieland B. HuttnerAbstract:Phosphatidylinositol transfer protein (PITP) and phospholipase D (PLD) stimulate the formation of constitutive secretory vesicles (CSVs) and immature secretory granules (ISGs) from the trans-Golgi network (TGN) in a cell-free system. The stimulatory effects of PITP and PLD are additive. Stimulation by either PITP or PLD is blocked by Geneticin, a member of the aminoglycoside antibiotics known to bind to phosphoinositides. Since the PLD we used is insensitive to Geneticin, our results suggest that phosphoinositides promote secretory vesicle formation as downstream effectors of both PITP and PLD, possibly via the recruitment of proteins mediating membrane budding and fission.
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Cooperativity of phosphatidylinositol transfer protein and phospholipase D in secretory vesicle formation from the TGN--phosphoinositides as a common denominator?
FEBS letters, 1997Co-Authors: Oliver Tüscher, Christoph Lorra, Barend Bouma, Karel W. A. Wirtz, Wieland B. HuttnerAbstract:Phosphatidylinositol transfer protein (PITP) and phospholipase D (PLD) stimulate the formation of constitutive secretory vesicles (CSVs) and immature secretory granules (ISGs) from the trans-Golgi network (TGN) in a cell-free system. The stimulatory effects of PITP and PLD are additive. Stimulation by either PITP or PLD is blocked by Geneticin, a member of the aminoglycoside antibiotics known to bind to phosphoinositides. Since the PLD we used is insensitive to Geneticin, our results suggest that phosphoinositides promote secretory vesicle formation as downstream effectors of both PITP and PLD, possibly via the recruitment of proteins mediating membrane budding and fission.