Allosteric inhibitor development targeting HIV-1 integrase.
Allosteric inhibitor development targeting HIV-1 integrase.
复制标题
靶向HIV-1整合酶的变构抑制剂开发。
DOI：
10.1002/cmdc.201000443
复制
发表时间：
2011-02-07
期刊：
影响因子：
3.4
通讯作者：
Neamati, Nouri
中科院分区：
文献类型：
--
作者：
Al-Mawsawi, Laith Q.;Neamati, Nouri
HIV-1整合酶（IN）是病毒复制的三种必需酶之一，也是抗逆转录病毒药物发现和开发的重点。勤奋的研究导致了链转移特定化学类IN抑制剂的开发，其中两种化合物，raltegravir和elvitegravir，在迄今为止发现的任何IN抑制剂的美国FDA批准过程中推进得最远。默克公司（Merck & Co.）开发的Raltegravir已获得美国FDA批准用于HIV-1治疗，而吉利德科学公司（Gilead Sciences）和日本烟草公司（Japan Tobacco）开发的elvitegravir已进入III期临床试验。虽然这无疑是HIV-1 IN药物发现领域的成功，但在临床使用这些化合物后，HIV-1 IN链转移特异性耐药病毒株的开发有望在患者中实现。此外，由于IN活性位点的重叠结合取向和两种化合物的等效抑制机制，交叉耐药病毒株的发展将加剧链转移特异性IN耐药性的问题。这种必然性将导致HIV-1治疗经验丰富的患者没有可用的in靶向治疗选择。变构靶向IN抑制剂的开发为发现有效对抗IN链转移耐药病毒株的化合物提供了一种极其有利的方法，并且可能与所有FDA批准的抗逆转录病毒HIV-1疗法（包括IN链转移特异性化合物）显示协同作用。在这里，我们回顾了变构抑制IN的概念，以及已经研究的结合非活性位点区域抑制IN功能的小分子。
HIV-1 integrase (IN) is one of three essential enzymes for viral replication, and a focus of ardent antiretroviral drug discovery and development efforts. Diligent research has led to the development of the strand transfer specific chemical class of IN inhibitors, with two compounds from this group, raltegravir and elvitegravir, advancing the farthest in the US FDA approval process for any IN inhibitor discovered thus far. Raltegravir, developed by Merck & Co., has been US FDA approved for HIV-1 therapy, whereas elvitegravir, developed by Gilead Sciences and Japan Tobacco, has reached Phase III clinical trials. Although this is an undoubted success for the HIV-1 IN drug discovery field, the development of HIV-1 IN strand transfer specific drug resistant viral strains upon clinical use of the compounds is expected in the patient. Furthermore the problem of strand transfer specific IN drug resistance will be exacerbated by the development of cross-resistant viral strains due to an overlapping binding orientation at the IN active site and an equivalent inhibitory mechanism for the two compounds. This inevitability will result in no available IN-targeted therapeutic options for HIV-1 treatment experienced patients. The development of allosterically targeted IN inhibitors presents an extremely advantageous approach for the discovery of compounds effective against IN strand transfer drug resistant viral strains, and would likely show synergy with all available FDA approved antiretroviral HIV-1 therapeutics, including the IN strand transfer specific compounds. Here we review the concept of allosteric IN inhibition, and the small molecules that have been investigated to bind non-active site regions to inhibit IN function.
登录
查看更多内容
DOI：
10.1073/pnas.150220297
发表时间：
2000-07-18
影响因子：
11.1
作者：
Chen, JCH;Krucinski, J;Stroud, RM
通讯作者：
Stroud, RM
DOI：
10.1073/pnas.0506924102
发表时间：
2005-11-29
影响因子：
11.1
作者：
Cherepanov, P;Ambrosio, ALB;Engelman, A
通讯作者：
Engelman, A
影响因子：
11.5
作者：
Croxtall, Jamie D.;Scott, Lesley J.
通讯作者：
Scott, Lesley J.
影响因子：
3.7
作者：
Al-Mawsawi, Laith Q.;Hombrouck, Anneleen;Neamati, Nouri
通讯作者：
Neamati, Nouri
影响因子：
4.8
作者：
Basavapathruni, A;Bailey, CM;Anderson, KS
通讯作者：
Anderson, KS