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Alex Azhayev - One of the best experts on this subject based on the ideXlab platform.
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Characterization of antisense Oligonucleotide-peptide conjugates with negative ionization electrospray mass spectrometry and liquid chromatography-mass spectrometry.
Journal of Pharmaceutical and Biomedical Analysis, 2003Co-Authors: Unni Tengvall, Maxim Antopolsky, Seppo Auriola, Alex Azhayev, Leo BiegelmanAbstract:Covalent post-synthesis or solid-phase conjugation of peptides to Oligonucleotides has been reported as a possible method of delivering antisense Oligonucleotides into cells. While synthesis strategies for preparing these conjugates have been widely addressed, few detailed reports on their structural characterization have been published. This paper discusses the negative ion electrospray ionization mass spectrometric (ESI-MS) and liquid chromatography-mass spectrometric (LC-MS) analysis of various peptide-Oligonucleotide conjugates ranging from small T(6)-nucleopeptides to large peptide-Oligonucleotide Phosphorothioate conjugates and ribozyme-peptide hybrids (3-13 kDa). Molecular weight determination with mass errors of 0.1-3.1 amu were conducted, employing on-line IP-RP-HPLC and high m/z range mode to facilitate the analysis of large compounds and difficult modifications.
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Towards a general method for the stepwise solid-phase synthesis of peptide-Oligonucleotide conjugates
Tetrahedron Letters, 2002Co-Authors: Maxim Antopolsky, Elena Azhayeva, Unni Tengvall, Alex AzhayevAbstract:Abstract Three peptide–Oligonucleotide Phosphorothioate hybrids were synthesized using a new approach for stepwise solid-phase synthesis of conjugates. This method utilizes commercially available N α -Fmoc amino acids for peptide synthesis and a new solid support. Three specific modifications of the solid-phase were made after the peptide and before the Oligonucleotide assembly.
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Synthesis of peptide-Oligonucleotide Phosphorothioate conjugates by convergent or stepwise solid-phase strategies.
Nucleosides Nucleotides and Nucleic Acids, 2001Co-Authors: Maxim Antopolsky, Alex AzhayevAbstract:A convergent strategy was employed to link eight 10-27-mer peptides to Oligonucleotide Phosphorothioates, resulting in twenty-six various conjugates. A stepwise synthesis strategy for the preparation of peptide-Oligonucleotide Phosphorothioate conjugates, employing Fmoc peptide chemistry, was developed and applied to the synthesis of four conjugates. Three of these conjugates contained either a 10 or 16-mer peptide, incorporating either 2 or 3 arginine residues, respectively.
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stepwise solid phase synthesis of peptide Oligonucleotide Phosphorothioate conjugates employing fmoc peptide chemistry
Tetrahedron Letters, 2000Co-Authors: Maxim Antopolsky, Alex AzhayevAbstract:Abstract A straightforward stepwise method for the preparation of peptide–Oligonucleotide Phosphorothioate conjugates, was developed, based on the highly efficient Fmoc peptide solid phase synthesis, followed by Oligonucleotide phosphorothiate chain assembly. The three conjugates synthesized contained 15- or 17-mer Oligonucleotide Phosphorothioates and 10- or 16-mer peptides, incorporating two or three arginine residues.
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Stepwise solid-phase synthesis of peptide–Oligonucleotide Phosphorothioate conjugates employing Fmoc peptide chemistry
Tetrahedron Letters, 2000Co-Authors: Maxim Antopolsky, Alex AzhayevAbstract:Abstract A straightforward stepwise method for the preparation of peptide–Oligonucleotide Phosphorothioate conjugates, was developed, based on the highly efficient Fmoc peptide solid phase synthesis, followed by Oligonucleotide phosphorothiate chain assembly. The three conjugates synthesized contained 15- or 17-mer Oligonucleotide Phosphorothioates and 10- or 16-mer peptides, incorporating two or three arginine residues.
Maxim Antopolsky - One of the best experts on this subject based on the ideXlab platform.
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Characterization of antisense Oligonucleotide-peptide conjugates with negative ionization electrospray mass spectrometry and liquid chromatography-mass spectrometry.
Journal of Pharmaceutical and Biomedical Analysis, 2003Co-Authors: Unni Tengvall, Maxim Antopolsky, Seppo Auriola, Alex Azhayev, Leo BiegelmanAbstract:Covalent post-synthesis or solid-phase conjugation of peptides to Oligonucleotides has been reported as a possible method of delivering antisense Oligonucleotides into cells. While synthesis strategies for preparing these conjugates have been widely addressed, few detailed reports on their structural characterization have been published. This paper discusses the negative ion electrospray ionization mass spectrometric (ESI-MS) and liquid chromatography-mass spectrometric (LC-MS) analysis of various peptide-Oligonucleotide conjugates ranging from small T(6)-nucleopeptides to large peptide-Oligonucleotide Phosphorothioate conjugates and ribozyme-peptide hybrids (3-13 kDa). Molecular weight determination with mass errors of 0.1-3.1 amu were conducted, employing on-line IP-RP-HPLC and high m/z range mode to facilitate the analysis of large compounds and difficult modifications.
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Towards a general method for the stepwise solid-phase synthesis of peptide-Oligonucleotide conjugates
Tetrahedron Letters, 2002Co-Authors: Maxim Antopolsky, Elena Azhayeva, Unni Tengvall, Alex AzhayevAbstract:Abstract Three peptide–Oligonucleotide Phosphorothioate hybrids were synthesized using a new approach for stepwise solid-phase synthesis of conjugates. This method utilizes commercially available N α -Fmoc amino acids for peptide synthesis and a new solid support. Three specific modifications of the solid-phase were made after the peptide and before the Oligonucleotide assembly.
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Synthesis of peptide-Oligonucleotide Phosphorothioate conjugates by convergent or stepwise solid-phase strategies.
Nucleosides Nucleotides and Nucleic Acids, 2001Co-Authors: Maxim Antopolsky, Alex AzhayevAbstract:A convergent strategy was employed to link eight 10-27-mer peptides to Oligonucleotide Phosphorothioates, resulting in twenty-six various conjugates. A stepwise synthesis strategy for the preparation of peptide-Oligonucleotide Phosphorothioate conjugates, employing Fmoc peptide chemistry, was developed and applied to the synthesis of four conjugates. Three of these conjugates contained either a 10 or 16-mer peptide, incorporating either 2 or 3 arginine residues, respectively.
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stepwise solid phase synthesis of peptide Oligonucleotide Phosphorothioate conjugates employing fmoc peptide chemistry
Tetrahedron Letters, 2000Co-Authors: Maxim Antopolsky, Alex AzhayevAbstract:Abstract A straightforward stepwise method for the preparation of peptide–Oligonucleotide Phosphorothioate conjugates, was developed, based on the highly efficient Fmoc peptide solid phase synthesis, followed by Oligonucleotide phosphorothiate chain assembly. The three conjugates synthesized contained 15- or 17-mer Oligonucleotide Phosphorothioates and 10- or 16-mer peptides, incorporating two or three arginine residues.
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Stepwise solid-phase synthesis of peptide–Oligonucleotide Phosphorothioate conjugates employing Fmoc peptide chemistry
Tetrahedron Letters, 2000Co-Authors: Maxim Antopolsky, Alex AzhayevAbstract:Abstract A straightforward stepwise method for the preparation of peptide–Oligonucleotide Phosphorothioate conjugates, was developed, based on the highly efficient Fmoc peptide solid phase synthesis, followed by Oligonucleotide phosphorothiate chain assembly. The three conjugates synthesized contained 15- or 17-mer Oligonucleotide Phosphorothioates and 10- or 16-mer peptides, incorporating two or three arginine residues.
Sudhir Agrawal - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics and metabolism of an oligodeoxynucleotide Phosphorothioate (GEM91) in cynomolgus monkeys following intravenous infusion.
Antisense and Nucleic Acid Drug Development, 1998Co-Authors: J. Michael Grindel, Timothy J. Musick, Zhiwei Jiang, Allysen Roskey, Sudhir AgrawalAbstract:The pharmacokinetics and metabolism of an antisense Oligonucleotide Phosphorothioate (GEM91®) were studied in cynomolgus monkeys following intravenous infusion. [35S]-Labeled GEM91 was administered...
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Effect of aspirin on protein binding and tissue disposition of Oligonucleotide Phosphorothioate in rats
Journal of Drug Targeting, 1998Co-Authors: Sudhir Agrawal, Xueshu Zhang, Qiuyin Cai, Ekambar R. Kandimalla, Alisa K. Manning, Zhiwie Jiang, T. Marcel, Ruiwen ZhangAbstract:AbstractPharmacokinetic studies of Phosphorothioate oligodeoxynucleotides (PS-Oligonucleotides) in animals show that following intravenous administration, PS-Oligonucleotide clears out rapidly from the plasma and is distributed to majority of the organs. PS-Oligonucleotides are bound to plasma proteins extensively. This study was aimed to determine the effect of aspirin, a commonly used drug, on pharmacokinetics of PS-Oligonucleotides. In the present study, PS-Oligonucleotide was administered to rats that had received aspirin by gavage. Pharmacokinetic study shows that if PS-Oligonucleotide was administered following aspirin administration in rats, a) plasma pharmacokinetic parameters (t1/2α?, t1/2β, AUC, etc.) had lower values, b) tissue disposition was different, and c) rate and route of elimination was affected in animals compared to rats receiving PS-Oligonucleotide alone. This finding suggests that pharmacokinetics of PS-Oligonucleotides can be affected with certain class of drugs, which may have dir...
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The multiple inhibitory mechanisms of GEM 91, a gag antisense Phosphorothioate Oligonucleotide, for human immunodeficiency virus type 1.
AIDS Research and Human Retroviruses, 1997Co-Authors: Koushi Yamaguchi, Sudhir Agrawal, Béla Papp, Dezhen Zhang, Ahmad N. Ali, Randal A. ByrnAbstract:GEM 91 (gene expression modulator) is a 25-mer Oligonucleotide Phosphorothioate complementary to the gag initiation site of HIV-1. GEM 91 has been studied in various in vitro cell culture models to examine inhibitory effects on different stages of HIV-1 replication. Experiments were focused on the binding of virions to the cell surface, inhibition of virus entry, reverse transcription (HIV DNA production), inhibition of steady state viral mRNA levels, inhibition of virus production from chronically infected cells, and inhibition of HIV genome packaging within virions. Experiments were also performed in vitro in an attempt to generate strains of HIV with reduced sensitivity to GEM 91. We observed sequence-dependent inhibition of virus entry/reverse transcription and a reduction in steady state viral RNA levels. We also observed sequence-independent inhibition of virion binding to cells and inhibition of virus production by chronically infected cells. Using in vitro methods that were successful in generating HIV strains with reduced sensitivity to AZT, we were unable to generate strains with reduced sensitivity to GEM 91.
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Effect of different chemically modified oligodeoxynucleotides on immune stimulation
Biochemical Pharmacology, 1996Co-Authors: Qiuyan Zhao, Zhiwei Jiang, Jamal Temsamani, Patricia L. Iadarola, Sudhir AgrawalAbstract:Based on previous studies that certain Oligonucleotides can stimulate cell proliferation and immunoglobulin production, this study was carried out to establish the relationship between the stimulatory effect and the chemical modification of the Oligonucleotide. First, the effects of Oligonucleotide and analogs on immune stimulation were studied in vitro using murine splenic lymphocytes. Our results show that cell proliferation and immunoglobulin production (IgG and IgM) depend on the sequence and the chemical modification of the Oligonucleotide. Phosphorothioate oligodeoxynucleotides displayed a greater stimulatory effect than partially modified Phosphorothioate Oligonucleotides. Second, we studied the effects of these chemically modified olionucleotides after injection in mice. Massive splenomegaly and stimulation of cell proliferation were observed with some Phosphorothioate Oligonucleotides. These effect were minimized markedly by chimeric and hybrid Oligonucleotides. We also demonstrate that in vitro the effects of Oligonucleotides on murine lymphocytes were unaffected by T cell depletion, suggesting that Oligonucleotides exert their effects mainly on the B cells.
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in vivo stability disposition and metabolism of a hybrid Oligonucleotide Phosphorothioate in rats
Biochemical Pharmacology, 1995Co-Authors: Ruiwen Zhang, Zhiwei Jiang, Hui Zhao, Xueshu Zhang, Robert B. Diasio, Ivan Habus, Radhakrishnan P. Iyer, L U Zhihong, Sudhir AgrawalAbstract:Oligodeoxynucleotide Phosphorothioates containing segments of 2′-O-methyloligoribo-nucleotide Phosphorothioates at both 3′- and 5′-ends (hybrid Oligonucleotide) have been shown to be potent antisense agents. In the present study, in vivo biostability, disposition, and excretion of a 25-mer hybrid Oligonucleotide were determined in rats after i.v. bolus administration of the 35S-labeled Oligonucleotide at a dose of 30 mg/kg. The plasma disappearance curve for the hybrid Oligonucleotide could be described by a two-compartmental model, with half-lives of 0.34 and 52.02 hr, respectively. The majority of the radioactivity in plasma was associated with the intact hybrid Oligonucleotide. Urinary excretion represented the major pathway of elimination, with 21.98 ± 3.21% (mean ± SD) of the administered dose excreted within 24 hr and 38.13 ± 2.99% over 240 hr post-dosing. The majority of the radioactivity in urine was associated with the degradative products with lower molecular weights, but the intact form was also detected by HPLC analysis. Fecal excretion was a minor pathway of elimination with 2.34 ± 0.13% of the administered dose excreted over 24 hr and 6.74 ± 0.40% over 240 hr post-dosing. A wide tissue distribution of hybrid Oligonucleotide was observed based on radioactivity levels, and analysis by HPLC showed that the majority of the radioactivity in tissues was associated with the intact hybrid Oligonucleotide. Further analyses of the experimental data provided a comprehensive pharmacokinetic analysis of hybrid Oligonucleotide in each tissue. Compared with a previously examined oligodeoxynucleotide Phosphorothioate (GEM 91) that has a similar nucleotide sequence, the hybrid Oligonucleotide had a shorter distribution half-life and a longer elimination half-life, based on the quantitation of radioactivity in plasma. Although it had a similar tissue distribution pattern compared with other Oligonucleotide Phosphorothioates such as GEM 91, the hybrid Oligonucleotide was more stable in vivo, which may be important in the development of antisense Oligonucleotides as therapeutic agents.
Jin Yan Tang - One of the best experts on this subject based on the ideXlab platform.
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Solid phase synthesis of Oligonucleotide Phosphorothioate analogues using 3-methyl-1,2,4-dithiazolin-5-one (MEDITH) as a new sulfur-transfer reagent
Tetrahedron Letters, 1999Co-Authors: Zhaoda Zhang, Alexandra Nichols, Jimmy X. Tang, Yonxin Han, Jin Yan TangAbstract:Abstract A new sulfur-transfer reagent, 3-methyl-1,2,4-dithiazolin-5-one (MEDITH), has been used for the synthesis of Oligonucleotide Phosphorothioates via solid phase phosphoramidite approach.
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Solid phase synthesis of Oligonucleotide Phosphorothioate analogues using bis(ethoxythiocarbonyl)tetrasulfide as a new sulfur-transfer reagent
Tetrahedron Letters, 1998Co-Authors: Zhaoda Zhang, Alexandra Nichols, Jimmy X. Tang, Mazen Alsbeti, Jin Yan TangAbstract:Abstract A new sulfur-transfer reagent, bis(ethoxythiocarbonyl)tetrasulfide ( 1 ), has been prepared and used for the synthesis of Oligonucleotide Phosphorothioates via solid phase phosphoramidite approach.
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Evaluation of Sulfur-Transfer Reagents for Large Scale Synthesis of Oligonucleotide Phosphorothioate Analogues
Nucleosides and Nucleotides, 1997Co-Authors: Zhaoda Zhang, Alexandra Nichols, Jimmy X. Tang, Mazen Alsbeti, Jin Yan TangAbstract:Abstract Several sulfur-transfer reagents have been evaluated for large scale synthesis of Oligonucleotide Phosphorothioate analogues, in which 3-ethoxy-1, 2-dithiazoline-5-one (EDITH, 5) shows potential as an alternative to Beaucage reagent.
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Enzymatic Synthesis of Stereoregular (All Rp) Oligonucleotide Phosphorothioate and Its Properties
Nucleosides Nucleotides and Nucleic Acids, 1995Co-Authors: Jin Yan Tang, Allysen Roskey, Sudhir AgrawalAbstract:Abstract A protocol has been established for the synthesis of stereoregular (all Rp) Oligonucleotide Phosphorothioates. A 25-mer oligodeoxynucleotide Phosphorothioate has been synthesized and studied for biophysical and biochemical properties.
Zhaoda Zhang - One of the best experts on this subject based on the ideXlab platform.
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Solid phase synthesis of Oligonucleotide Phosphorothioate analogues using 3-methyl-1,2,4-dithiazolin-5-one (MEDITH) as a new sulfur-transfer reagent
Tetrahedron Letters, 1999Co-Authors: Zhaoda Zhang, Alexandra Nichols, Jimmy X. Tang, Yonxin Han, Jin Yan TangAbstract:Abstract A new sulfur-transfer reagent, 3-methyl-1,2,4-dithiazolin-5-one (MEDITH), has been used for the synthesis of Oligonucleotide Phosphorothioates via solid phase phosphoramidite approach.
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Solid phase synthesis of Oligonucleotide Phosphorothioate analogues using bis(ethoxythiocarbonyl)tetrasulfide as a new sulfur-transfer reagent
Tetrahedron Letters, 1998Co-Authors: Zhaoda Zhang, Alexandra Nichols, Jimmy X. Tang, Mazen Alsbeti, Jin Yan TangAbstract:Abstract A new sulfur-transfer reagent, bis(ethoxythiocarbonyl)tetrasulfide ( 1 ), has been prepared and used for the synthesis of Oligonucleotide Phosphorothioates via solid phase phosphoramidite approach.
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Evaluation of Sulfur-Transfer Reagents for Large Scale Synthesis of Oligonucleotide Phosphorothioate Analogues
Nucleosides and Nucleotides, 1997Co-Authors: Zhaoda Zhang, Alexandra Nichols, Jimmy X. Tang, Mazen Alsbeti, Jin Yan TangAbstract:Abstract Several sulfur-transfer reagents have been evaluated for large scale synthesis of Oligonucleotide Phosphorothioate analogues, in which 3-ethoxy-1, 2-dithiazoline-5-one (EDITH, 5) shows potential as an alternative to Beaucage reagent.
