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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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Crystallographic analysis of the binding modes of thiazoloisoindolinone non-nucleoside inhibitors to hiv-1 reverse transcriptase and comparison with modeling studies

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JOURNAL OF MEDICINAL CHEMISTRY 1999年第19期42卷 3845-3851页

作者： Ren, JS Esnouf, RM Hopkins, AL Stuart, DI Stammers, DK Univ Oxford Mol Biophys Lab Oxford OX1 3QU England Oxford Ctr Mol Sci Oxford OX1 3QT England

We have determined the crystal structures of thiazoloisoindolinone non-nucleoside inhibitors in complex with hiv-1 reverse transcriptase to high-resolution limits of 2.7 Angstrom (BM +21.1326) and 2.52 Angstrom (BM +50.0934). We find that the binding modes of this series of inhibitors closely resemble that of "two-ring'' non-nucleoside reverse transcriptase inhibitors. The structures allow rationalization of stereochemical requirements, structure-activity data, and drug resistance data. Comparisons with our previous structures suggest modifications to the inhibitors that might improve resilience to drug-resistant mutant forms of reverse transcriptase. Comparison with earlier modeling studies reveals that the predicted overlap of thiazoloisoindolinones with TIBO was largely correct, while that with nevirapine was significantly different.

关键词：结晶学 X线 hiv逆转录酶/拮抗剂和抑制剂 hiv逆转录酶/代谢吲哚类/化学吲哚类/代谢模型化学模型分子蛋白质结合蛋白质构象逆转录酶抑制剂/化学逆转录酶抑制剂/代谢构效关系噻唑类/化学噻唑类/代谢

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Lamivudine (3TC) resistance in hiv-1 reverse transcriptase involves steric hindrance with β-branched amino acids

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第18期96卷 10027-10032页

作者： Sarafianos, SG Das, K Clark, AD Ding, JP Boyer, PL Hughes, SH Arnold, E Ctr Adv Biotechnol & Med Piscataway NJ 08854 USA Rutgers State Univ Dept Chem Piscataway NJ 08854 USA NCI Frederick Canc Res & Dev Ctr Adv Biosci Labs Basic Res Program Frederick MD 21702 USA

An important component of triple-drug anti-AIDS therapy is 2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine). Single mutations at residue 184 of the reverse transcriptase (RT) in hiv cause high-level resistance to 3TC and contribute to the failure of anti-AIDS combination therapy. We have determined crystal structures of the 3TC-resistant mutant hiv-1 RT (M184I) in both the presence and absence of a DNA/DNA template-primer, In the absence of a DNA substrate, the wild-type and mutant structures are very similar. However, comparison of crystal structures of M184I mutant and wild-type hiv-1 RT with and without DNA reveals repositioning of the template-primer in the M184I/DNA binary complex and other smaller changes in residues in the dNTP-binding site. On the basis of these structural results, we developed a model that explains the ability of the 3TC-resistant mutant M184I to incorporate dNTPs but not the nucleotide analog 3TCTP. In this model, steric hindrance is expected for NRTIs with beta- or L- ring configurations, as with the enantiomer of 3TC that is used in therapy. Steric conflict between the oxathiolane ring of 3TCTP and the side chain of P-branched amino acids (Val, Ile, Thr) at position 184 perturbs inhibitor binding, leading to a reduction in incorporation of the analog. The model can also explain the 3TC resistance of analogous hepatitis B polymerase mutants. Repositioning of the template-primer as observed in the binary complex (M184I/DNA) may also occur in the catalytic ternary complex (M184I/DNA/3TCTP) and contribute to 3TC resistance by interfering with the formation of a catalytically competent closed complex.

关键词：别构调节氨基酸序列氨基酸取代保守序列二聚作用抗药性微生物 hiv逆转录酶/化学 hiv逆转录酶/遗传学 hiv逆转录酶/代谢 hiv-1/药物作用 hiv-1/酶学 hiv-1/遗传学拉米夫定/化学拉米夫定/药理学大分子物质模型分子分子序列数据核酸构象点突变蛋白质构象 RNA 病毒/化学 RNA 病毒/代谢模板遗传人类

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Incorporation of 4-thiothymidine into DNA by the klenow fragment and hiv-1 reverse transcriptase

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2000年第9期10卷 907-910页

作者： Rao, TVS Haber, MT Sayer, JM Jerina, DM NIDDKD Bioorgan Chem Lab NIH Bethesda MD 20892 USA

The 5'-triphosphate of 4-thiothymidine (4S-TTP) is an excellent substrate for the Klenow fragment of Escherichia coli DNA polymerase I and hiv-1 reverse transcriptase with values of k(cat)/K-m within a factor of similar to 3 of those for TTP. A large UV change (Delta epsilon = -9770 M-1 cm(-1) at 340 nm) associated with incorporation of 4S-TMP into nucleic acid duplexes makes possible a rapid, continuous spectrophotometric assay of the reaction progress. (C) 2000 Published by Elsevier Science Ltd.

关键词：碱基配对/药物作用 DNA/生物合成 DNA/化学 DNA聚合酶Ⅰ/代谢 DNA引物大肠杆菌/酶学 hiv逆转录酶/代谢动力学分光光度法紫外线模板遗传胸苷/类似物和衍生物胸苷/化学

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A second target for the peptoid Tat/transactivation response element inhibitor CGP64222: Inhibition of human immunodeficiency virus replication by blocking CXC-chemokine receptor 4-mediated virus entry

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MOLECULAR PHARMACOLOGY 2000年第1期57卷 116-124页

作者： Daelemans, D Schols, D Witvrouw, M Pannecouque, C Hatse, S van Dooren, S Hamy, F Klimkait, T De Clercq, E Vandamme, AM Katholieke Univ Leuven Rega Inst Med Res B-3000 Louvain Belgium Novartis Pharmaceut Pharma Res Basel Switzerland

The peptoid CGP64222 has been previously demonstrated to inhibit the human immunodeficiency virus (hiv) Tat/transactivation response element complex formation. It has previously been shown that CGP64222 selectively inhibits hiv-1 long terminal repeat-driven gene expression and hiv-1(LAV) replication in lymphocytes. Here, we show that CGP64222 inhibits the replication of a wide range of laboratory strains of hiv-1 and hiv-2 in MT-4 cells. However, CGP64222 proved inactive in MT-4 cells against hiv-1 strains that are resistant to the bicyclams. The bicyclams are known to specifically interact with CXC-chemokine receptor 4, the main coreceptor used by T-tropic hiv strains to enter the cells. Mechanism of action studies revealed that CGP64222 can inhibit the hiv replicative cycle, also through a selective interaction with the CXC-chemokine receptor 4 coreceptor.

关键词：抗hiv药/药理学抗体单克隆/免疫学结合竞争性生物转运钙/代谢趋化因子CXCL12 趋化因子 CXC/代谢剂量效应关系药物基因表达调控病毒/药物作用基因产物 tat/拮抗剂和抑制剂基因产物 tat/遗传学基因产物 tat/代谢基因 tat/药物作用 hiv逆转录酶/药物作用 hiv逆转录酶/代谢 hiv-1/药物作用 hiv-1/生理学 hiv-2/药物作用 hiv-2/生理学白细胞单核/药物作用白细胞单核/病毒学寡肽类/药理学类肽类受体 CXCR4/拮抗剂和抑制剂受体 CXCR4/免疫学转录激活/药物作用转染肿瘤细胞培养的病毒装配/药物作用病毒复制/药物作用 tat基因产物人免疫缺陷病毒人类

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