Biswas D K, Mhashilkar A M, Ewaniuk D S, Pezza J A, Oh L M, Kannangara G S, Tius M A, Pardee A B
Division of Cell Growth and Regulation, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Aug 15;18(5):426-34. doi: 10.1097/00042560-199808150-00003.
The small molecule S9a was derived from an established tumor necrosis factor-alpha (TNF-alpha) inhibitor (Canventol) by replacement of the isopropylidine group with a phenyl ring. S9a at 10 to 100 nM inhibited HIV production as potently as 3'-azido-3'-deoxythymidine (AZT), an inhibitor of viral reverse transcriptase. Furthermore, S9a and AZT in combination, at noncytoxic concentrations strongly inhibited HIV-1 replication that was more than additive and substantially prolonged the appearance of virus both in acutely infected CD4+ lymphocytes (SupT) in culture and in peripheral blood mononuclear cells (PBMCs) infected with a primary HIV-1 isolate. S9a inhibited TNF-alpha promoter-driven reporter gene activity. It was proposed that the mechanism of antiviral action of S9a was on the host cell, by blocking TNF-alpha transcription via a Tat-induced tar-independent loop, which decreases downstream NF-kappaB activation of HIV-1 long terminal repeat (LTR). S9a was superior to the first generation compound Canventol, which was superior to the natural compound sarcophytol A, demonstrating that further structure-based enhancement of potency of these compounds is feasible. This study suggests a therapeutic approach against AIDS by application of two drugs, one against a cellular and the other a viral target, which may provide an approach to the problem of frequent emergence of resistant variants to combinations of drugs that target only HIV genes.
小分子S9a是由一种已有的肿瘤坏死因子-α（TNF-α）抑制剂（Canventol）衍生而来，通过用苯环取代异亚丙基。10至100 nM的S9a抑制HIV产生的效力与病毒逆转录酶抑制剂3'-叠氮-3'-脱氧胸苷（AZT）相当。此外，S9a和AZT以无细胞毒性的浓度联合使用，能强烈抑制HIV-1复制，这种抑制作用超过相加效应，并且在培养的急性感染CD4+淋巴细胞（SupT）以及感染原发性HIV-1分离株的外周血单核细胞（PBMC）中，能显著延长病毒出现的时间。S9a抑制TNF-α启动子驱动的报告基因活性。有人提出，S9a的抗病毒作用机制是作用于宿主细胞，通过Tat诱导的非依赖tar的环阻断TNF-α转录，从而减少HIV-1长末端重复序列（LTR）下游NF-κB的激活。S9a优于第一代化合物Canventol，而Canventol又优于天然化合物鼠尾藻醇A，这表明基于结构进一步增强这些化合物的效力是可行的。本研究提出了一种治疗艾滋病的方法，即应用两种药物，一种针对细胞靶点，另一种针对病毒靶点，这可能为解决仅靶向HIV基因的药物组合频繁出现耐药变异体的问题提供一种途径。
