硫代磷酸酯寡核苷酸在生物流体中的代谢动力学。
Kinetics of phosphorothioate oligonucleotide metabolism in biological fluids.
作者信息
Gilar M, Belenky A, Smisek D L, Bourque A, Cohen A S
机构信息
Hybridon, Inc., 620 Memorial Drive, Cambridge, MA 02139, USA.
出版信息
Nucleic Acids Res. 1997 Sep 15;25(18):3615-20. doi: 10.1093/nar/25.18.3615.
Abstract
The in vitro stability and metabolism of GEM[91, a 25mer phosphorothioate antisense oligonucleotide complementary to the gag mRNA region of HIV-1, was investigated using capillary electrophoresis (CE). The in vitro degradation of the parent compound at 37 degrees C was followed over the course of 120 h in human plasma. A CE method using laser-induced fluorescence detection was able to detect 5'-end intact metabolites including the parent compound extracted from biological fluids. Because the primary metabolic pathway is believed to be via 3'-exonuclease activity, the results of this study were compared with the stability of the compound in a solution containing 3'-exonuclease. The numerical solution of sequential first-order reactions was used to obtain kinetic parameters. Exonuclease digestion of the parent compound, as measured using an automated CE-UV instrument, yielded striking similarities between the two in vitro systems as well as between in vitro and in vivo systems.
摘要
使用毛细管电泳（CE）研究了GEM[91]（一种与HIV-1的gag mRNA区域互补的25聚体硫代磷酸酯反义寡核苷酸）的体外稳定性和代谢情况。在人血浆中，于37℃下对母体化合物的体外降解进行了120小时的跟踪监测。一种采用激光诱导荧光检测的CE方法能够检测到从生物流体中提取的包括母体化合物在内的5'-端完整代谢产物。由于主要代谢途径被认为是通过3'-外切核酸酶活性，本研究结果与该化合物在含有3'-外切核酸酶的溶液中的稳定性进行了比较。采用连续一级反应的数值解来获得动力学参数。使用自动CE-UV仪器测量母体化合物的外切核酸酶消化情况，结果显示两个体外系统之间以及体外和体内系统之间存在显著相似性。
相似文献
1
Kinetics of phosphorothioate oligonucleotide metabolism in biological fluids.硫代磷酸酯寡核苷酸在生物流体中的代谢动力学。
Nucleic Acids Res. 1997 Sep 15;25(18):3615-20. doi: 10.1093/nar/25.18.3615.
2
Study of phosphorothioate-modified oligonucleotide resistance to 3'-exonuclease using capillary electrophoresis.使用毛细管电泳研究硫代磷酸酯修饰的寡核苷酸对3'-外切核酸酶的抗性
J Chromatogr B Biomed Sci Appl. 1998 Aug 28;714(1):13-20. doi: 10.1016/s0378-4347(98)00160-1.
3
Sequence-specific RNase H cleavage of gag mRNA from HIV-1 infected cells by an antisense oligonucleotide in vitro.体外利用反义寡核苷酸对来自HIV-1感染细胞的gag mRNA进行序列特异性核糖核酸酶H切割。
Nucleic Acids Res. 1998 Dec 15;26(24):5670-5. doi: 10.1093/nar/26.24.5670.
4
A nonradioisotope approach to study the in vivo metabolism of phosphorothioate oligonucleotides.一种研究硫代磷酸酯寡核苷酸体内代谢的非放射性同位素方法。
Antisense Nucleic Acid Drug Dev. 1997 Feb;7(1):13-22. doi: 10.1089/oli.1.1997.7.13.
5
In vivo metabolic profile of a phosphorothioate oligodeoxyribonucleotide.硫代磷酸酯寡脱氧核糖核苷酸的体内代谢概况。
Antisense Nucleic Acid Drug Dev. 1997 Jun;7(3):159-65. doi: 10.1089/oli.1.1997.7.159.
6
Impact of 3'-exonuclease stereoselectivity on the kinetics of phosphorothioate oligonucleotide metabolism.
Antisense Nucleic Acid Drug Dev. 1998 Feb;8(1):35-42. doi: 10.1089/oli.1.1998.8.35.
7
Preconcentration and separation of antisense oligonucleotides by on-column isotachophoresis and capillary electrophoresis in polymer-filled capillaries.在填充聚合物的毛细管中通过柱上等速电泳和毛细管电泳对反义寡核苷酸进行预浓缩和分离。
Electrophoresis. 1998 Jun;19(8-9):1445-51. doi: 10.1002/elps.1150190839.
8
Antisense oligodeoxynucleotide phosphorothioate complementary to Gag mRNA blocks replication of human immunodeficiency virus type 1 in human peripheral blood cells.与Gag mRNA互补的硫代磷酸反义寡脱氧核苷酸可阻断1型人类免疫缺陷病毒在人外周血细胞中的复制。
Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):7942-6. doi: 10.1073/pnas.91.17.7942.
9
Pharmacokinetic properties of several novel oligonucleotide analogs in mice.几种新型寡核苷酸类似物在小鼠体内的药代动力学特性
J Pharmacol Exp Ther. 1996 May;277(2):923-37.
10
Hairpin antisense oligonucleotides containing 2'-methoxynucleosides with base-pairing in the stem region at the 3'-end: penetration, localization, and Anti-HIV activity.在3'端茎区具有碱基配对的含2'-甲氧基核苷的发夹反义寡核苷酸：穿透、定位及抗HIV活性
Biochem Biophys Res Commun. 1996 Nov 12;228(2):623-31. doi: 10.1006/bbrc.1996.1707.
引用本文的文献
1
Investigating the Impact of Delivery Routes for Exon Skipping Therapies in the CNS of DMD Mouse Models.研究外显子跳跃疗法在 DMD 小鼠模型中枢神经系统中的递送途径的影响。
Cells. 2023 Mar 15;12(6):908. doi: 10.3390/cells12060908.
2
Clinical Pharmacokinetics of Approved RNA Therapeutics.已批准的 RNA 治疗药物的临床药代动力学。
Int J Mol Sci. 2023 Jan 1;24(1):746. doi: 10.3390/ijms24010746.
3
and studies of antisense oligonucleotides - a review.反义寡核苷酸的研究——综述
RSC Adv. 2020 Sep 17;10(57):34501-34516. doi: 10.1039/d0ra04978f. eCollection 2020 Sep 16.
4
Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases.用于儿科适应症的反义寡核苷酸在幼年哥廷根小型猪中的安全性测试，包括对关键核酸酶个体发育的评估。
Pharmaceutics. 2021 Sep 10;13(9):1442. doi: 10.3390/pharmaceutics13091442.
5
Recent developments in the characterization of nucleic acids by liquid chromatography, capillary electrophoresis, ion mobility, and mass spectrometry (2010-2020).近十年来液相色谱、毛细管电泳、离子淌度和质谱技术在核酸分析中的应用进展。
J Sep Sci. 2021 Jan;44(1):340-372. doi: 10.1002/jssc.202000833. Epub 2020 Oct 15.
6
Studying in vitro metabolism of the first and second generation of antisense oligonucleotides with the use of ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.采用超高效液相色谱-四极杆飞行时间质谱联用技术研究第一代和第二代反义寡核苷酸的体外代谢。
Anal Bioanal Chem. 2020 Nov;412(27):7453-7467. doi: 10.1007/s00216-020-02878-0. Epub 2020 Aug 27.
7
Current Status of Antisense Oligonucleotide-Based Therapy in Neuromuscular Disorders.神经肌肉疾病中反义寡核苷酸治疗的现状。
Drugs. 2020 Sep;80(14):1397-1415. doi: 10.1007/s40265-020-01363-3.
8
Oligonucleotide analysis by hydrophilic interaction liquid chromatography-mass spectrometry in the absence of ion-pair reagents.无离子对试剂的亲水作用液相色谱-质谱法进行寡核苷酸分析。
J Chromatogr A. 2019 Jun 21;1595:39-48. doi: 10.1016/j.chroma.2019.02.016. Epub 2019 Feb 7.
9
The Use of Tricyclo-DNA Oligomers for the Treatment of Genetic Disorders.三环DNA寡聚体在遗传疾病治疗中的应用。
Biomedicines. 2017 Dec 22;6(1):2. doi: 10.3390/biomedicines6010002.
10
Pharmacology, pharmacokinetics, and metabolism of the DNA-decoy AYX1 for the prevention of acute and chronic post-surgical pain.用于预防急性和慢性术后疼痛的DNA诱饵AYX1的药理学、药代动力学和代谢
Mol Pain. 2017 Jan;13:1744806917703112. doi: 10.1177/1744806917703112.
本文引用的文献
1
A nonradioisotope approach to study the in vivo metabolism of phosphorothioate oligonucleotides.一种研究硫代磷酸酯寡核苷酸体内代谢的非放射性同位素方法。
Antisense Nucleic Acid Drug Dev. 1997 Feb;7(1):13-22. doi: 10.1089/oli.1.1997.7.13.
2
Antisense oligonucleotides: towards clinical trials.反义寡核苷酸：迈向临床试验
Trends Biotechnol. 1996 Oct;14(10):376-87. doi: 10.1016/0167-7799(96)10053-6.
3
Pharmacokinetic properties of several novel oligonucleotide analogs in mice.几种新型寡核苷酸类似物在小鼠体内的药代动力学特性
J Pharmacol Exp Ther. 1996 May;277(2):923-37.
4
Pharmacokinetics and tissue distribution in rats of an oligodeoxynucleotide phosphorothioate (GEM 91) developed as a therapeutic agent for human immunodeficiency virus type-1.一种作为人类免疫缺陷病毒1型治疗剂开发的硫代磷酸寡脱氧核苷酸（GEM 91）在大鼠体内的药代动力学和组织分布。
Biochem Pharmacol. 1995 Mar 30;49(7):929-39. doi: 10.1016/0006-2952(95)00010-w.
5
Review of in vivo pharmacokinetics and toxicology of phosphorothioate oligonucleotides.
J Clin Lab Anal. 1995;9(2):129-37. doi: 10.1002/jcla.1860090210.
6
Pharmacokinetics of an anti-human immunodeficiency virus antisense oligodeoxynucleotide phosphorothioate (GEM 91) in HIV-infected subjects.硫代磷酸反义寡脱氧核苷酸（GEM 91）在HIV感染受试者中的药代动力学。
Clin Pharmacol Ther. 1995 Jul;58(1):44-53. doi: 10.1016/0009-9236(95)90071-3.
7
Inhibition of replication and expression of human T-cell lymphotropic virus type III in cultured cells by exogenous synthetic oligonucleotides complementary to viral RNA.外源性合成的与病毒RNA互补的寡核苷酸对培养细胞中人嗜T细胞病毒III型复制和表达的抑制作用。
Proc Natl Acad Sci U S A. 1986 Jun;83(12):4143-6. doi: 10.1073/pnas.83.12.4143.
8
Bond order and charge localization in nucleoside phosphorothioates.
Science. 1985 May 3;228(4699):541-5. doi: 10.1126/science.2984773.
9
Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide.一种特定的寡脱氧核苷酸对劳氏肉瘤病毒复制和细胞转化的抑制作用。
Proc Natl Acad Sci U S A. 1978 Jan;75(1):280-4. doi: 10.1073/pnas.75.1.280.
Zotero 插件