Wang Dan, Lu Wuxun, Li Feng
Department of Biology and Microbiology, South Dakota State University, Brookings 57007, USA.
Department of Biology and Microbiology, South Dakota State University, Brookings 57007, USA ; Department of Veterinary and Biomedical Sciences, South Dakota State University, Brookings 57007, USA.
Acta Pharm Sin B. 2015 Nov;5(6):493-9. doi: 10.1016/j.apsb.2015.05.004. Epub 2015 Jun 11.
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.
尽管抗逆转录病毒疗法取得了重大进展，但在许多当前获批的人类免疫缺陷病毒（HIV）药物中观察到的耐药性增加和毒性表明，需要发现和开发具有新型作用机制的强效且安全的抗病毒药物。成熟抑制剂（MIs）代表了一类这样的新型HIV疗法。MIs抑制HIV-1 Gag加工级联反应的后期步骤，导致有缺陷的核心凝聚以及从受感染细胞中释放出无感染性的病毒颗粒，从而阻止感染扩散到新的细胞。MIs的临床概念验证是通过源自桦木酸的贝维拉马（bevirimat）（HIV-1 MIs原型）得以确立的。尽管由于天然存在的耐药性Gag多态性导致患者反应不一致，其在2010年停止了进一步的临床开发，但最近已发现了几种对表现出Gag多态性介导耐药性的病毒具有更高活性的第二代MIs，并正在HIV/AIDS患者中进行临床评估。在本综述中，描述了对HIV-1 MIs的当前认识，并综述了在阐明其作用机制、靶点鉴定以及第二代MIs开发方面取得的最新进展。
