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Site-specific incorporation of nucleoside analogs by HIV-1 reverse transcriptase and the template grip mutant P157S - Template interactions influence substrate recognition at the polymerase active site

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第1期275卷 359-366页

作者： Klarmann, GJ Smith, RA Schinazi, RF North, TW Preston, BD Univ Utah Dept Biochem Eccles Inst Human Genet Salt Lake City UT 84112 USA Univ Utah Dept Radiat Oncol Eccles Inst Human Genet Salt Lake City UT 84112 USA Univ Utah Huntsman Canc Inst Salt Lake City UT 84112 USA Emory Univ Sch Med Dept Pediat Decatur GA 30033 USA Emory Univ Sch Med Georgia Vet Affairs Res Ctr AIDS & HIV Invect Decatur GA 30033 USA Univ Calif Davis Ctr Comparat Med Davis CA 95616 USA

Studies of drug-resistant reverse transcriptases (RTs) reveal the roles of specific structural elements and amino acids in polymerase function. To characterize better the effects of RT/template interactions on dNTP substrate recognition, we examined the sensitivity of human immunodeficiency virus type 1 (HIV-1) RT containing a new mutation in a "template grip" residue (P157S) to the 5'-triphosphates of (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC), (-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC), and 3'-azido-3'-deoxythymidine (AZT). A primer extension assay was used to monitor quantitatively drug monophosphate incorporation opposite each of multiple target sites. Wild-type and P157S RTs had similar catalytic activities and processivities on heteropolymeric RNA and DNA templates. When averaged over multiple template sites, P157S RT was 2-7-fold resistant to the 5'-triphosphates of 3TC, FTC, and AZT, Each drug triphosphate inhibited polymerization more efficiently on the DNA template compared with an RNA template of identical sequence. Moreover, chain termination by 3TC and FTC was strongly influenced by template sequence context. Incorporation of FTC and 3TC monophosphate varied up to 10-fold opposite 7 different G residues in the DNA template, and the P157S mutation altered this site specificity. In summary, these data identify Pro(157) as an important residue affecting nucleoside analog resistance and suggest that interactions between RT and the template strand influence dNTP substrate recognition at the RT active site. Our findings are discussed within the context of the HIV-1 RT structure.

关键词：催化域胞苷三磷酸/类似物和衍生物胞苷三磷酸/代谢胞苷三磷酸/药理学双脱氧核苷酸类剂量效应关系药物抗药性 HIV逆转录酶/药物作用 HIV逆转录酶/遗传学 HIV逆转录酶/代谢 HIV-1/酶学拉米夫定/类似物和衍生物突变脯氨酸/遗传学逆转录酶抑制剂/代谢逆转录酶抑制剂/药理学硫代核苷类/代谢噻吩类胸腺嘧啶核苷酸类/代谢胸腺嘧啶核苷酸类/药理学转录遗传/药物作用扎昔他宾/类似物和衍生物扎昔他宾/代谢齐多夫定/类似物和衍生物齐多夫定/代谢齐多夫定/药理学

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Structural requirements for potent human spermicidal activity of dual-function aryl phosphate derivative of bromo-methoxy zidovudine (Compound WHI-07)

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BIOLOGY OF REPRODUCTION 2000年第1期62卷 37-44页

作者： D'Cruz, OJ Venkatachalam, TK Uckun, FM Howard Hughes Med Inst Drug Discovery Program Dept Reprod Biol St Paul MN 55113 USA Howard Hughes Med Inst Drug Discovery Program Dept Chem St Paul MN 55113 USA Howard Hughes Med Inst Drug Discovery Program Dept Virol St Paul MN 55113 USA

WHI-07, a novel bromo-methoxy-substituted aryl phosphate derivative of zidovudine (ZDV), is a potent dual-function contraceptive agent. Although the bromo-methoxy functional groups in the thymine ring of ifs ZDV ape very important for its sperm-immobilizing activity (SIA), the importance of the esterification of the phosphate group with an amino acid side chain and the identity of the para substituent in the aryl moiety remain unclear. In the present study, we have synthesized 23 new analogues of WHI-07 by replacing the alanine (Ala) side chain with different amino acids containing nonpolar side chains, namely tryptophan (Trp), proline (Pro), phenylalanine (Phe), leucine (Leu), methionine (Met), valine (Val), or glycine (Cly). The pam substituents on the aryl moiety included bromo, chloro, fluoro, nitro, or methoxy groups. The SIA of each of the 23 WHI-07 analogues was evaluated by computer assisted sperm analysis. The potential cytotoxicity of these compounds against normal human ectocervical and endocervical epithelial cells was evaluated using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) cell viability assays. The replacement of the Ala side chain of WHI-07 with Val, Leu, or Phe led to a complete loss of SIA (EC50 values > 500 mu M), whereas replacement with Trp reduced the SIA by 4-fold. The presence of para substituents on the phenyl moiety led to significant alterations in SIA. The anti-human immunodeficiency virus (HIV) activity of Trp-containing WHI-07 analogues was also diminished. Our finding highlights the necessity of Ala side chain and the presence of electron-withdrawing para-bromo substituent on the phenyl moiety in addition to bromo-methoxy functionalization groups on the thymine ring in order for the phosphoramidate derivatives of ZDV to be effective dual-function spermicidal agents. Unlike the detergent-type microbicide, nonoxynol-9, which was cytotoxic to normal human ectocervical and endocervical epithelial cells (IC50 valu

关键词：抗HIV药/化学抗HIV药/药理学子宫颈/药物作用剂量效应关系药物上皮细胞/药物作用分子结构精子能动性/药物作用杀精子药/化学杀精子药/药理学构效关系胸苷一磷酸/类似物和衍生物胸苷一磷酸/化学胸苷一磷酸/药理学齐多夫定/类似物和衍生物齐多夫定/化学齐多夫定/药理学女(雌)性人类男(雄)性

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Synthesis and antiviral activity of amino acid carbamate derivatives of AZT

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NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2000年第1-2期19卷 87-100页

作者： Chang, SL Griesgraber, G Abraham, TW Garg, T Song, H Zimmerman, CL Wagner, CR Univ Minnesota Coll Pharm Dept Med Chem Minneapolis MN 55455 USA Univ Minnesota Coll Pharm Dept Pharmaceut Minneapolis MN 55455 USA Univ Minnesota Coll Pharm Program Microbiol Immunol & Mol Pathobiol Minneapolis MN 55455 USA

Lipophilic amino acid methyl ester and methyl amide carbamates of 3'-azido-3'-deoxythymidine (AZT) were synthesized and their anti-HIV-l activity in PBMCs was determined. The methyl amides were more potent (EC(50)s = 1.8 - 4.0 mu M) than the methyl esters (EC(50)s = 2.0 - 20 mu M). Carbamate hydrolysis by cell lysates and liberation of AZT was not observed for representative methyl ester or methyl amide AZT carbamates. No evidence of direct inhibition of HIV reverse transcriptase or integrase was observed.

关键词：立体异构现象病毒复制/药物作用齐多夫定/类似物和衍生物

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Synthesis, in vitro anti-breast cancer activity, and intracellular decomposition of amino acid methyl ester and alkyl amide phosphoramidate monoesters of 3′-azido-3′-deoxythymidine (AZT)

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JOURNAL OF MEDICINAL CHEMISTRY 2000年第11期43卷 2266-2274页

作者： Iyer, VV Griesgraber, GW Radmer, MR McIntee, EJ Wagner, CR Univ Minnesota Dept Med Chem Coll Pharm Minneapolis MN 55455 USA

We report the synthesis and anticancer activity of a series of AZT phosphoramidate monoesters containing amino acid methyl ester (3a-11a) and N-alkyl amide (3b-11b, 9c-9f) moieties. The aromatic amino acid methyl esters were found to be more cytotoxic than the aliphatic analogues toward MCF-7 cells (human pleural effusion breast adenocarcinoma cell line). A marked stereochemical preference for the L-amino acid stereochemistry was also observed in MCF-7 cells. There was no consistent enhancement of cytotoxicity of the methyl amides over the corresponding methyl esters. AZT and the two AZT aromatic amino acid methyl ester phosphoramidates 8a and 9a were found to be more cytotoxic toward MCF-7 cells than to CEM cells (human T-cell lymphoblastic leukemia). The selective cytotoxicity toward MCF-7 cells may be associated with greater intracellular levels of phosphoramidate monoester and/or phosphorylated AZT.

关键词：抗肿瘤药/化学合成抗肿瘤药/化学抗肿瘤药/药理学乳腺肿瘤/药物疗法药物筛选试验抗肿瘤酯类肿瘤细胞培养的齐多夫定/类似物和衍生物齐多夫定/药理学女(雌)性人类

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'Double-drugs' - A new class of prodrug form of an HIV protease inhibitor conjugated with a reverse transcriptase inhibitor by a spontaneously cleavable linker

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2000年第11期10卷 1227-1231页

作者： Matsumoto, H Hamawaki, T Ota, H Kimura, T Goto, T Sano, K Hayashi, Y Kiso, Y Kyoto Pharmaceut Univ Ctr Frontier Res Med Sci Dept Med Chem Yamashima Ku Kyoto 6078412 Japan Osaka Med Coll Dept Microbiol Takatsuki Osaka 5698686 Japan

We designed and synthesized a new series of prodrug-type anti-HIV agents consisting of a peptidomimetic HIV protease inhibitor conjugated with a nucleoside reverse transcriptase inhibitor in an effort to enhance the antiviral activity. For the conjugation, a series of linkers that conjoin the two different classes of inhibitors have been investigated. Conjugates using a succinyl amino acid linker were shown to release the parent components via the spontaneous imide formation at a faster rate compared to conjugates using a glutaryl amino acid linker, as expected from the energetically favorable cyclization to the five-membered ring. Herein, we report a new 'double-drug' 4b (KNI-1039) with a glutarylglycine linker, which exhibited extremely potent anti-HIV activity compared with that of the individual components. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：抗HIV药/化学抗HIV药/药理学 HIV蛋白酶抑制药/化学 HIV-1/药物作用微生物敏感性试验药物前体/化学逆转录酶抑制剂/化学噻唑类/化学噻唑类/药理学齐多夫定/类似物和衍生物齐多夫定/化学齐多夫定/药理学人类

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Cyclosaligenyl-2′,3′-didehydro-2′,3′-dideoxythymidine monophosphate:: Efficient intracellular delivery of d4TMP

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MOLECULAR PHARMACOLOGY 2000年第5期58卷 928-935页

作者： Balzarini, J Aquaro, S Knispel, T Rampazzo, C Bianchi, V Perno, CF De Clercq, E Meier, C Katholieke Univ Leuven Rega Inst Med Res B-3000 Louvain Belgium Univ Roma Tor Vergata Dept Expt Med Rome Italy Univ Hamburg Inst Organ Chem D-2000 Hamburg Germany Univ Padua Dept Biol Padua Italy Ist Ric & Cura Carattere Sci Lazzaro Spallanzani Rome Italy

Cyclosaligenyl-2',3'-didehydro-2',3'-dideoxythymidine-5'-monophosphate (cycloSal-d4TMP) is a potent and selective inhibitor of human immunodeficiency virus replication in cell culture and differs from other nucleotide prodrug approaches in that it is designed to selectively deliver the nucleotide 5'-monophosphate by a controlled, chemically induced hydrolysis. Its antiviral efficacy in cell culture is at least as good as, if not superior to, that of d4T. CycloSal-d4TMP was found to lead to the efficient intracellular release of d4TMP in a variety of cell lines, including both wild-type CEM and thymidine kinase-deficient CEM/TK- cells. Under similar experimental conditions, exposure of CEM/TK- cells to d4T failed to result in significant d4TTP levels. The intracellular conversion of cycloSal- d4TMP proved to be both time and dose dependent. The half-life of d4TTP generated intracellularly from d4T- or cycloSal-d4TMP-treated CEM cells was similar to 3.5 h, and the intracellular ratios of d4TTP/d4TMP in cells exposed to cycloSal-d4TMP gradually increased from 1 to 3.4 upon prolonged incubation. Radiolabeled cycloSal- d4TMP could be separated as its two R-p and S-p diastereomers on high-performance liquid chromatography. The R-p diastereomer of cycloSal- d4TMP was 3- to 7-fold more efficient in releasing d4TMP and generating d4TTP than the S-p cycloSal- d4TMP diastereomer. This correlated well with the 5-fold more pronounced antiviral activity of the R-p diastereomer versus the S-p diastereomer. d4TMP is a poor substrate for the cytosolic 5'(3')-deoxyribonucleotidase (V-max/K-m for d4TMP: 0.08 of V-max/K-m for dTMP) and is only slowly hydrolyzed to d4T. This contributes to the efficient conversion of the prodrug of d4TTP.

关键词： 5'-核苷酸酶/代谢抗HIV药/代谢抗HIV药/药理学培养基双脱氧核苷酸类半衰期氢离子浓度白细胞单核/代谢巨噬细胞/代谢单核细胞/代谢司他夫定/类似物和衍生物司他夫定/代谢司他夫定/药理学胸苷/类似物和衍生物胸苷/代谢胸苷/药理学胸苷激酶/代谢胸苷一磷酸/代谢胸腺嘧啶核苷酸类/代谢时间因素氚肿瘤细胞培养的齐多夫定/类似物和衍生物齐多夫定/代谢人类

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Modifying human thymidylate kinase to potentiate azidothymidine activation

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第50期274卷 35289-35292页

作者： Brundiers, R Lavie, A Veit, T Reinstein, J Schlichting, I Ostermann, N Goody, RS Konrad, M Max Planck Inst Mol Physiol Dept Phys Biochem D-44227 Dortmund Germany Max Planck Inst Biophys Chem Dept Mol Genet D-37070 Gottingen Germany

Based on the knowledge of the crystal structures of yeast and Escherichia coli thymidylate kinases (TmpKs) and the observation that TmpK from E. coli can phosphorylate azidothymidine monophosphate (AZT-MP) much more efficiently than either the yeast or the highly homologous human enzyme, we have engineered yeast and human TmpKs to obtain enzymes that have dramatically improved AZT-MP phosphorylation properties. These modified enzymes have properties that make them attractive candidates for gene therapeutic approaches to potentiating the action of AZT as an inhibitor of human immunodeficiency virus (HIV) replication. In particular, insertion of the lid domain of the bacterial TmpK into the human enzyme results in a pronounced change of the acceptance of AZT-MP such that it is now phosphorylated even faster than TMP.

关键词：氨基酸序列氨基酸取代克隆分子双脱氧核苷酸类大肠杆菌/酶学动力学分子序列数据诱变定点核苷一磷酸激酶/化学核苷一磷酸激酶/代谢重组蛋白质类/化学重组蛋白质类/代谢酿酒酵母菌/酶学序列比对序列同源性氨基酸底物特异性胸腺嘧啶核苷酸类/药代动力学齐多夫定/类似物和衍生物齐多夫定/药代动力学人类

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Synthesis, lipophilicity and anti-HIV activity of a new brominated analog of zidovudine

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NUCLEOSIDES & NUCLEOTIDES 1999年第3期18卷 337-351页

作者： Motura, M Salomón, H Moroni, G Wainberg, M Briñón, MC Univ Nacl Cordoba Fac Ciencias Quim Dept Farm RA-5000 Cordoba Argentina Univ Buenos Aires Fac Med Dept Microbiol Ctr Nacl ReferenciaSIDA RA-1121 Buenos Aires DF Argentina McGill Univ Jewish Gen Hosp AIDS Ctr Lady Davis Inst Montreal PQ H3T 1E2 Canada

A novel cyclic bromine zidovudine analog, (-)-trans-(5S,6S)-5-bromo-6,5'-epoxy-5,6-dihydro-3'-azido-3'-deoxythymidine (2), and its diastereoisomer (+)-trans-(5R,6R)-(3) were synthesized and characterized by spectroscopic methods, obtaining 3 in very low yields. The major product 2 presents a selectivity index (CCID50/IC50) similar to zidovudine but 55.5 times with higher lipophilicity, which should increase the ability of 2 to cross the blood-brain barrier by a non facilitated diffusion mechanism.

关键词：抗HIV药/化学合成抗HIV药/化学抗HIV药/药理学细胞系细胞存活/药物作用细胞培养的药物稳定性胎血 HIV-1/药物作用单核细胞/细胞学单核细胞/药物作用立体异构现象齐多夫定/类似物和衍生物人类

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Intracellular metabolism of CycloSaligenyl 3′-azido-2′,3′-dideoxythymidine monophosphate, a prodrug of 3′-azido-2′,3′-dideoxythymidine (zidovudine)

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MOLECULAR PHARMACOLOGY 1999年第6期56卷 1354-1361页

作者： Balzarini, J Naesens, L Aquaro, S Knispel, T Perno, CF De Clercq, E Meier, C Katholieke Univ Leuven Rega Inst Med Res B-3000 Louvain Belgium Univ Roma Tor Vergata Dept Expt Med Rome Italy Univ Hamburg Inst Organ Chem D-2000 Hamburg Germany IRCCS Rome Italy

The administration of CycloSaligenyl 3'-azido-2',3'-dideoxythymidine monophosphate (CycloSal-AZTMP) to CEM cells resulted in a concentration- and time-dependent conversion to the 5'-monophosphate (AZTMP), 5'-diphosphate (AZTDP), and 5'-triphosphate (AZTTP) derivatives. High ratios of AZTMP/AZTTP were found in the CEM cell cultures treated with CycloSal-AZTMP. The intracellular T-1/2 of AZTTP in CEM cell cultures treated with either AZT and CycloSal-AZTMP was approximately 3 h. A variety of human T- and B-lymphocyte cell lines efficiently converted the prodrug to the AZT metabolites, whereas peripheral blood lymphocytes and primary monocyte/macrophages showed at least 10-fold lower metabolic conversion of the prodrug. CycloSal-AZTMP failed to generate marked levels of AZT metabolites in thymidine kinase-deficient CEM/TK- cells, an observation that is in agreement with the substantial loss of antiviral activity of CycloSal-AZTMP in CEM/TK- cells. The inability of CycloSal-AZTMP to generate AZTMP in CEM/TK- cells is presumably due to a relatively high hydrolysis rate of AZTMP to the parent nucleoside AZT, combined with the inability of CEM/TK- cells to phosphorylate AZT to AZTMP through the cytosolic salvage enzyme thymidine kinase.

关键词：抗HIV药/代谢细胞系培养基/代谢双脱氧核苷酸类药物稳定性氢离子浓度药物前体/代谢药物前体/药理学司他夫定/类似物和衍生物司他夫定/代谢胸苷激酶/代谢胸腺嘧啶核苷酸类/代谢氚肿瘤细胞培养的齐多夫定/类似物和衍生物齐多夫定/代谢齐多夫定/药理学人类

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Synthesis and anti-retroviral activity of O,O′-bis(3′-azido-2′,3′-dideoxythymidin-5′-yl) phosphoramidate derivatives

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NUCLEOSIDES & NUCLEOTIDES 1999年第10期18卷 2317-2325页

作者： Kers, I Stawinski, J Girardet, JL Imbach, JL Périgaud, C Gosselin, G Aubertin, AM Univ Stockholm Arrhenius Lab Dept Organ Chem S-10691 Stockholm Sweden Univ Montpellier 2 Chim Bioorgan Lab CNRS UMR 5625 F-34095 Montpellier 5 France Fac Med Strasbourg Inst Virol INSERM U74 F-67000 Strasbourg France

A simple and efficient protocol for the preparation of various symmetrical dinucleoside phosphoramidates derived from AZT, is presented. It consists of the phosphonylation of AZT with phosphonic acid in the presence of DCC to produce the symmetrical H-phosphonate diester, followed by its oxidative conversion to various phosphoramidate analogues. The synthesized compounds were evaluated for their anti-HIV activity in different cell cultures.

关键词：酰胺类/化学抗HIV药/化学合成抗HIV药/化学抗HIV药/药理学细胞培养的 HIV-1/药物作用核苷类/化学合成核苷类/化学核苷类/药理学磷酸类/化学药物前体/化学合成药物前体/化学药物前体/药理学病毒复制/药物作用齐多夫定/类似物和衍生物人类

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