Potentiation of inhibition of wild-type and mutant human immunodeficiency virus type 1 reverse transcriptases by combinations of nonnucleoside inhibitors and D- and L-(β)-dideoxynucleoside triphosphate analogs
Potentiation of inhibition of wild-type and mutant human immunodeficiency virus type 1 reverse transcriptases by combinations of nonnucleoside inhibitors and D- and L-(β)-dideoxynucleoside triphosphate analogs
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DOI：
10.1128/aac.45.4.1192-1200.2001
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发表时间：
2001-04-01
影响因子：
4.9
通讯作者：
Spadari, S
中科院分区：
文献类型：
--
作者：
Maga, C;Hübscher, U;Spadari, S
逆转录酶（RT）抑制剂的组合目前用于抗人类免疫缺陷病毒疗法中，以预防或延迟抗性病毒的出现并改善针对携带抗性突变的病毒酶的功效。药物间相互作用可导致正面（相加或协同抑制）或负面（拮抗相互作用、协同毒性）效应。阐明药物相互作用的性质将有助于合理选择联合使用的抗逆转录病毒药物。在这项研究中，核苷和非核苷抑制剂的不同组合，包括D-和L-（β）-脱氧-和-双脱氧核苷三磷酸类似物，已经在体外RT试验中针对重组野生型RT或携带临床相关非核苷抑制剂耐药突变的RT进行了测试（L1001，K103 N，Y1811），以及相互作用的性质评估了这些关联的协同作用（协同作用或拮抗作用），结果表明（i）组合的协同作用并不总是受到所用单个药物的同等影响，（ii）协同组合可以提高耐药突变酶对所用单一药物的敏感性，（iii）核苷RT抑制剂的L-（β）-对映体与非核苷RT抑制剂组合时具有协同作用，以及（iv）每种药物相对效力的组合间和组合内比较可用于突出每种药物对所观察到的协同作用的不同贡献。
Combinations of reverse transcriptase (RT) inhibitors are currently used in anti-human immunodeficiency virus therapy in order to prevent or delay the emergence of resistant virus and to improve the efficacy against viral enzymes carrying resistance mutations. Drug-drug interactions can result in either positive (additive or synergistic inhibition) or adverse (antagonistic interaction, synergistic toxicity) effects. Elucidation of the nature of drug interaction would help to rationalize the choice of antiretroviral agents to be used in combination. In this study, different combinations of nucleoside and nonnucleoside inhibitors, including D- and L-(beta)-deoxy- and -dideoxynucleoside triphosphate analogues, have been tested in in vitro RT assays against either recombinant wild-type RT or RT bearing clinically relevant nonnucleoside inhibitor resistance mutations (L1001, K103N, Y1811), and the nature of the interaction (either synergistic or antagonistic) of these associations was evaluated, The results showed that (i) synergy of a combination was not always equally influenced by the individual agents utilized, (ii) a synergistic combination could improve the sensitivity profile of a drug-resistant mutant enzyme to the single agents utilized, (iii) L-(beta)-enantiomers of nucleoside RT inhibitors were synergistic when combined with nonnucleoside RT inhibitors, and (iv) inter- and intracombination comparisons of the relative potencies of each drug could be used to highlight the different contributions of each drug to the observed synergy.