Pharmacological intervention of HIV-1 maturation.
Pharmacological intervention of HIV-1 maturation.
复制标题
HIV-1成熟的药理干预。
DOI：
10.1016/j.apsb.2015.05.004
复制
发表时间：
2015-11
期刊：
影响因子：
--
通讯作者：
Li F
中科院分区：
文献类型：
--
作者：
Wang D;Lu W;Li F
尽管在抗逆转录病毒治疗方面取得了重大进展，但在目前批准的许多人类免疫缺陷病毒(HIV)药物中观察到的耐药性和毒性不断增加，这表明需要发现和开发具有新作用机制的有效、安全的抗病毒药物。成熟抑制药(MIs)代表了这样一类新的艾滋病毒治疗方法。MI抑制HIV-1 Gag处理级联反应的后期步骤，导致有缺陷的核心凝聚和从受感染细胞释放非传染性病毒颗粒，从而阻止感染向新细胞的传播。MI的临床概念验证是用白桦酸衍生的Bevirimat建立的，Bevirimat是HIV-1 MI的原型。尽管由于自然产生的GAG基因多态性导致患者缺乏统一的反应，它在2010年停止了进一步的临床开发，但最近发现了几种对表现出GAG基因多态介导的耐药性的病毒具有更好活性的第二代MI，并正在对HIV/AID患者进行临床评估。本文综述了人类免疫缺陷病毒1型管理信息系统的研究现状，并对第二代管理信息系统的作用机制、靶点识别和发展等方面的研究进展进行了综述。成熟抑制药(MI)代表了一类新的HIV治疗方法。本文综述了目前对HIV-1MI的认识，并综述了在阐明其作用机制、靶点识别和第二代MI的发展方面的最新进展。
Despite significant advances in antiretroviral therapy, increasing drug resistance and toxicities observed among many of the current approved human immunodeficiency virus (HIV) drugs indicate a need for discovery and development of potent and safe antivirals with a novel mechanism of action. Maturation inhibitors (MIs) represent one such new class of HIV therapies. MIs inhibit a late step in the HIV-1 Gag processing cascade, causing defective core condensation and the release of non-infectious virus particles from infected cells, thus blocking the spread of the infection to new cells. Clinical proof-of-concept for the MIs was established with betulinic acid derived bevirimat, the prototype HIV-1 MI. Despite the discontinuation of its further clinical development in 2010 due to a lack of uniform patient response caused by naturally occurring drug resistance Gag polymorphisms, several second-generation MIs with improved activity against viruses exhibiting Gag polymorphism mediated resistance have been recently discovered and are under clinical evaluation in HIV/AID patients. In this review, current understanding of HIV-1 MIs is described and recent progress made toward elucidating the mechanism of action, target identification and development of second-generation MIs is reviewed. Maturation inhibitors (MI) represent one of new classes of HIV therapies. In this review, current understanding of HIV-1 MIs is described and recent progress made toward elucidating the mechanism of action, target identification, and development of second-generation MIs are reviewed.