新兴的药物靶点的抗逆转录病毒治疗。
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李维斯JD,不大AJ
新兴的药物靶点的抗逆转录病毒治疗。
药。2005;65 (13):1747 - 66。
- PubMed ID
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16114975 (在PubMed]
- 文摘
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目前抗逆转录病毒治疗(ART)的目标包括病毒酶逆转录酶和蛋白酶。针对这些酶抑制剂的组合的使用可以减少病毒载量为长期和延缓疾病进展。然而,并发症的艺术,包括对当前药物病毒耐药性的出现,推动新的抗逆转录病毒药物的发展目标不仅逆转录酶和蛋白酶酶新靶点。事实上,enfuvirtide,针对病毒包膜蛋白抑制剂(Env)最近被批准用于联合治疗在个人不应对现有的抗逆转录病毒药物。对艺术新兴药物靶点包括:(i)抑制剂,直接或间接目标Env;(2)HIV整合酶的酶;和(3)抑制剂的成熟目标蛋白酶酶的底物。Env介导病毒进入靶细胞通过一个多步过程,提出了三种不同的目标为抑制病毒和cellular-specific代理。首先,附件病毒粒子通过非特异性相互作用和CD4细胞表面绑定可以被抑制剂,包括cyanovirin-N cyclotriazadisulfonamide类似物,PRO 2000, TNX 355 PRO 542。此外,百时美施贵宝806可以阻止CD4-induced构象变化。 Secondly, Env interactions with the co-receptor molecules can be targeted by CCR5 antagonists including SCH-D, maraviroc (UK 427857) and aplaviroc (GW 873140), and the CXCR4 antagonist AMD 070. Thirdly, fusion of viral and cellular membranes can be inhibited by peptides such as enfuvirtide and tifuvirtide (T 1249). The development of entry inhibitors has been rapid, with an increasing number entering clinical trials. Moreover, some entry inhibitors are also being evaluated as candidate microbicides to prevent mucosal transmission of HIV. The integrase enzyme facilitates the integration of viral DNA into the host cell genome. The uniqueness and specificity of this reaction makes integrase an attractive drug target. However, integrase inhibitors have been slow to reach clinical development, although recent contenders, including L 870810, show promise. Inhibitors that target viral maturation via a unique mode of action, such as PA 457, also have potential. In addition, recent advances in our understanding of cellular pathways involved in the life cycle of HIV have also identified novel targets that may have potential for future antiretroviral intervention, including interactions between the cellular proteins APOBEC3G and TSG101, and the viral proteins Vif and p6, respectively. In summary, a number of antiretroviral agents in development make HIV entry, integration and maturation emerging drug targets. A multifaceted approach to ART, using combinations of inhibitors that target different steps of the viral life cycle, has the best potential for long-term control of HIV infection. Furthermore, the development of microbicides targeting HIV holds promise for reducing HIV transmission events.