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Virus maturation as a new HIV-1 therapeutic target.

机译:病毒成熟作为一种新的HIV-1治疗靶标。

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摘要

Development of novel therapeutic targets against HIV-1 is a high research priority owing to the serious clinical consequences associated with acquisition of resistance to current antiretroviral drugs. The HIV-1 structural protein Gag represents a potential new therapeutic target as it plays a central role in virus particle production yet is not targeted by any of the antiretroviral drugs approved at present. The Gag polyprotein precursor multimerizes to form immature particles that bud from the infected cell. Concomitant with virus release, the Gag precursor undergoes proteolytic processing by the viral protease to generate the mature Gag proteins, which include capsid (CA). Once liberated from the Gag polyprotein precursor, CA molecules interact to reassemble into a condensed conical core, which organizes the viral RNA genome and several viral proteins to facilitate virus replication in the next round of infection. Correct Gag proteolytic processing and core assembly are therefore essential for virus infectivity. In this review, we discuss new strategies to inhibit maturation by targeting proteolytic cleavage sites in Gag or CA-CA interactions required for core formation. The identification and development of lead maturation inhibitors are highlighted.
机译:由于获得对当前抗逆转录病毒药物的耐药性会导致严重的临床后果,因此针对HIV-1的新型治疗靶标的开发是一项高度的研究重点。 HIV-1结构蛋白Gag代表了潜在的新治疗靶标,因为它在病毒颗粒生产中起着核心作用,但目前尚未被任何批准的抗逆转录病毒药物作为靶标。 Gag多蛋白前体多聚形成未成熟的颗粒,从受感染的细胞中萌发。与病毒释放同时,Gag前体通过病毒蛋白酶进行蛋白水解处理,以生成成熟的Gag蛋白,​​其中包括衣壳(CA)。一旦从Gag多蛋白前体中释放出来,CA分子就会相互作用,重新组装成一个压缩的圆锥形核心,从而组织了病毒RNA基因组和几种病毒蛋白,从而促进了下一轮感染中的病毒复制。因此,正确的Gag蛋白水解加工和核心组装对于病毒感染至关重要。在这篇综述中,我们讨论了通过靶向核心形成所需的Gag或CA-CA相互作用中的蛋白水解切割位点来抑制成熟的新策略。铅成熟抑制剂的鉴定和开发工作突出。

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