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首页> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >New developments in anti-HIV chemotherapy
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New developments in anti-HIV chemotherapy

机译：抗HIV化疗的新进展

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Virtually all the compounds that are currently used, or are subject of advanced clinical trials, for the treatment of human immunodeficiency virus (HIV) infections, belong to one of the following classes: (i) nucleosideucleotide reverse transcriptase inhibitors (NRTIs): i.e. zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine [(-)FTC], tenofovir disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e. nevirapine, delavirdine, efavirenz, emivirine; and (iii) protease inhibitors (PIs): i.e. saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and lopinavir. In addition to the reverse transcriptase (RT) and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polycarboxylates, polyoxometalates, polynucleotides, and negatively charged albumins); (ii) viral entry, through blockade of the viral coreceptors CXCR4 [bicyclam (AMD3100) derivatives] and CCR5 (TAK-779 derivatives); (iii) virus-cell fusion, through binding to the viral envelope glycoprotein gp41 (T-20, T-1249); (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA)]; (v) proviral DNA integration, through integrase inhibitors such as 4-aryl-2,4-dioxobutanoic acid derivatives; (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (flavopiridol, fluoroquinolones). Also, various new NRTIs, NNRTIs and PIs have been developed that possess, respectively: (i) improved metabolic characteristics (i.e. phosphoramidate and cyclosaligenyl pronucleotides by-passing the first phosphorylation step of the NRTIs), (ii) increased activity ["second" or "third" generation NNRTIs (i.e. TMC-125, DPC-083)] against those HIV strains that are resistant to the "first" generation NNRTIs, or (iii) as in the case of PIs, a different, nonpeptidic scaffold [i.e. cyclic urea (mozenavir), 4-hydroxy-2-pyrone (tipranavir)]. Nonpeptidic PIs may be expected to inhibit HIV mutant strains that have become resistant to peptidomimetic PIs. Given the multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating the mode of action of these agents from cell-free enzymatic assays to intact cells. Two examples in point are L-chicoric acid and the nonapeptoid CGP6422, which were initially described as an integrase inhibitor or Tat antagonist, respectively, but later shown to primarily act as virus adsorption/entry inhibitors, the latter through blockade of CXCR4.
机译：实际上，目前用于治疗人类免疫缺陷病毒（HIV）感染或正在接受先进临床试验的所有化合物均属于以下类别之一：（i）核苷/核苷酸逆转录酶抑制剂（NRTIs）：即齐多夫定（AZT），去羟肌苷（ddI），扎西他滨（ddC），司他夫定（d4T），拉米夫定（3TC），阿巴卡韦（ABC），恩曲他滨[（-）FTC]，替诺福韦二吡呋酯富马酸盐; （ii）非核苷逆转录酶抑制剂（NNRTIs）：即奈韦拉平，地拉夫定，依非韦伦，阿米韦林; （iii）蛋白酶抑制剂（PIs）：即沙奎那韦，利托那韦，茚地那韦，奈非那韦，氨普那韦和洛匹那韦。除逆转录酶（RT）和蛋白酶反应外，HIV复制周期中的其他各种事件也可被视为化学疗法干预的潜在目标：（i）通过与病毒包膜糖蛋白gp120结合（多硫酸盐，聚磺酸盐，多羧酸盐，多金属氧酸盐，多核苷酸和带负电荷的白蛋白）; （ii）通过阻断病毒共受体CXCR4 [bicyclam（AMD3100）衍生物]和CCR5（TAK-779衍生物）进入病毒; （iii）通过与病毒包膜糖蛋白gp41（T-20，T-1249）结合而形成病毒-细胞融合; （iv）通过NCp7锌指靶向剂[2,2'-二硫代双苯甲酰胺（DIBAs），氮杂二酰胺（ADA）]进行病毒组装和拆卸; （v）通过整合酶抑制剂例如4-芳基-2,4-二氧代丁酸衍生物进行前病毒DNA整合; （vi）通过转录（反式激活）过程的抑制剂（黄酮吡啶醇，氟喹诺酮）进行病毒mRNA转录。同样，已开发出各种新的NRTI，NNRTI和PI，它们分别具有：（i）改善的代谢特性（即，通过NRTI的第一步磷酸化步骤的氨基磷酸酯和环saligenyl前核苷酸），（ii）活性增加[“ second”或“第三代” NNRTI（即TMC-125，DPC-083）针对那些对“第一”代NNRTI具有抗性的HIV毒株，或（iii）如在PI中，则使用不同的非肽支架[即环脲（莫泽那韦），4-羟基-2-吡喃酮（替普那韦）]。非肽类PIs有望抑制对拟肽类PIs产生抗性的HIV突变株。鉴于抗HIV试剂可与多种分子靶标相互作用，因此在将这些试剂的作用方式从无细胞酶法分析推导至完整细胞时应谨慎。两个例子就是L-衣康酸和非类肽CGP6422，它们最初分别被描述为整合酶抑制剂或Tat拮抗剂，但后来显示出主要起病毒吸附/进入抑制剂的作用，后者通过阻断CXCR4发挥作用。

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