首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Suppression of the breakthrough of human immunodeficiency virus type 1 (HIV-1) in cell culture by thiocarboxanilide derivatives when used individually or in combination with other HIV-1-specific inhibitors (i.e., TSAO derivatives).
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Suppression of the breakthrough of human immunodeficiency virus type 1 (HIV-1) in cell culture by thiocarboxanilide derivatives when used individually or in combination with other HIV-1-specific inhibitors (i.e., TSAO derivatives).

机译:硫代甲酰苯胺衍生物单独使用或与其他HIV-1特异性抑制剂(即TSAO衍生物)组合使用时,可抑制细胞培养物中人类免疫缺陷病毒1型(HIV-1)的突破。

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摘要

Five structurally related thiophene and furane analogues of the oxathiin carboxanilide derivative NSC 615985 (UC84) (designated UC10, UC68, UC81, UC42, and UC16) were identified as potent inhibitors of HIV-1 replication in cell culture and HIV-1 reverse transcriptase activity. These compounds were markedly active against a series of mutant HIV-1 strains, containing the Leu-100-->Ile, Val-106-->Ala, Glu-138-->Lys, or Tyr-181-->Cys mutations in their reverse transcriptase. However, the thiocarboxanilide derivatives selected for mutations at amino acid positions 100 (Leu-->Ile), 101 (Lys-->Ile/Glu), 103 (Lys-->Thr/Asp) and 141 (Gly-->Glu) in the HIV-1 reverse transcriptase. The compounds completely suppressed HIV-1 replication and prevented the emergence of resistant virus strains when used at 1.3-6.6 microM--that is, 10- to 25-fold lower than the concentration required for nevirapine and bis(heteroaryl)piperazine (BHAP) U90152 to do so. If UC42 was combined with the [2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"- oxathiole-2",2"-dioxide)]-beta-D-pentofuranosyl (TSAO) derivative of N3-methylthymine (TSAO-m3T), virus breakthrough could be prevented for a much longer time, and at much lower concentrations, than if the compounds were used individually. Virus breakthrough could be suppressed for even longer, and at lower drug concentrations, if BHAP was added to the combination of UC42 with TSAO-m3T, which points to the feasibility of two- or three-drug combinations in preventing virus breakthrough and resistance development.
机译:草酸羧甲酰苯胺衍生物NSC 615985(UC84)的五个与结构相关的噻吩和呋喃类似物(命名为UC10,UC68,UC81,UC42和UC16)被确定为在细胞培养物中抑制HIV-1复制和抑制HIV-1逆转录酶活性的有效抑制剂。 。这些化合物对一系列突变的HIV-1菌株具有显着活性,这些菌株包含Leu-100-> Ile,Val-106-> Ala,Glu-138-> Lys或Tyr-181-> Cys突变在他们的逆转录酶。但是,选择了在第100位(Leu-> Ile),101位(Lys-> Ile / Glu),103位(Lys-> Thr / Asp)和141位(Gly-> Glu)氨基酸突变的硫代甲酰苯胺衍生物。 )中的HIV-1逆转录酶。当以1.3-6.6 microM的浓度使用时,这些化合物完全抑制了HIV-1的复制并阻止了耐药病毒株的出现,即比奈韦拉平和双(杂芳基)哌嗪(BHAP)所需的浓度低10至25倍U90152这样做。如果将UC42与[2',5'-双-O-(叔丁基二甲基甲硅烷基)-3'-螺-5“-(4”-氨基-1“,2”-草硫醇-2“,2”结合使用N3-甲基胸腺嘧啶(TSAO-m3T)的-(二氧化物)]-β-D-戊呋喃糖基(TSAO)衍生物,与单独使用这些化合物相比,可以防止更长的时间且浓度更低的病毒突破。如果将BHAP加入UC42与TSAO-m3T的组合中,则可以在更长的药物浓度下抑制病毒的突破,并且在较低的药物浓度下,这表明两药或三药组合在预防病毒突破和耐药性发展方面的可行性。

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