Structure-activity relationships of a novel capsid targeted inhibitor of HIV-1 replication.
Structure-activity relationships of a novel capsid targeted inhibitor of HIV-1 replication.
复制标题
DOI：
10.1021/ci500437r
复制
发表时间：
2014-11-24
影响因子：
5.6
通讯作者：
Cocklin S
中科院分区：
文献类型：
--
作者：
Kortagere S;Xu JP;Mankowski MK;Ptak RG;Cocklin S
尽管高效抗逆转录病毒疗法（HAART）在治疗HIV/AIDS方面取得了相当大的成功，但累积的药物毒性和多药耐药病毒的发展使得有必要寻找具有新作用模式的新型抗逆转录病毒剂。HIV-1衣壳（CA）蛋白在结构和功能上都是一个可药用的靶点。我们最近设计了一种新的小分子抑制剂I-XW-053，使用基于杂化结构的方法以微摩尔亲和力阻断CA N-末端结构域之间的界面（NTD-NTD界面）。为了优化和提高I-XW-053的药效，我们采用配体效率法建立了I-XW-053系列化合物的构效关系。设计了I-XW-053的五十六种类似物，其可以基于其配体效率值被细分为四个不同的核心结构域，所述配体效率值被计算为结合效率（BEI）和表面效率（SEI）指数的比率。属于亚核心-3的化合物34在阻断原代人外周血单核细胞（PBMC）中的HIV-1复制方面显示出比I-XW-053高11倍的改善。表面等离子体共振实验证实了化合物34与纯化的HIV-1 CA蛋白的结合。化合物34和I-XW-053与HIV-1 CA蛋白的分子对接研究表明，它们都与NTD-NTD界面区结合，但结合模式不同，这一点通过定点突变研究得到进一步验证。
Despite the considerable successes of highly active antiretroviral therapy (HAART) for the treatment of HIV/AIDS, cumulative drug toxicities and the development of multidrug-resistant virus necessitate the search for new classes of antiretroviral agents with novel modes of action. The HIV-1 capsid (CA) protein has been structurally and functionally characterized as a druggable target. We have recently designed a novel small molecule inhibitor I-XW-053 using the hybrid structure based method to block the interface between CA N-terminal domains (NTD–NTD interface) with micromolar affinity. In an effort to optimize and improve the efficacy of I-XW-053, we have developed the structure activity relationship of I-XW-053 compound series using ligand efficiency methods. Fifty-six analogues of I-XW-053 were designed that could be subclassified into four different core domains based on their ligand efficiency values computed as the ratio of binding efficiency (BEI) and surface efficiency (SEI) indices. Compound 34 belonging to subcore-3 showed an 11-fold improvement over I-XW-053 in blocking HIV-1 replication in primary human peripheral blood mononuclear cells (PBMCs). Surface plasmon resonance experiments confirmed the binding of compound 34 to purified HIV-1 CA protein. Molecular docking studies on compound 34 and I-XW-053 to HIV-1 CA protein suggested that they both bind to NTD–NTD interface region but with different binding modes, which was further validated using site-directed mutagenesis studies.
登录
查看更多内容
影响因子：
6.7
作者：
Blair WS;Pickford C;Irving SL;Brown DG;Anderson M;Bazin R;Cao J;Ciaramella G;Isaacson J;Jackson L;Hunt R;Kjerrstrom A;Nieman JA;Patick AK;Perros M;Scott AD;Whitby K;Wu H;Butler SL
通讯作者：
Butler SL
影响因子：
4.8
作者：
Cartier, C;Sivard, P;Boyer, V
通讯作者：
Boyer, V
影响因子：
2.7
作者：
Fader, Lee D.;Landry, Serge;Simoneau, Bruno
通讯作者：
Simoneau, Bruno
影响因子：
3.5
作者：
Jin, Yinxue;Tan, Zhiwu;Yang, Ming
通讯作者：
Yang, Ming
影响因子：
64.8
作者：
Pertel, Thomas;Hausmann, Stephane;Morger, Damien;Zueger, Sara;Guerra, Jessica;Lascano, Josefina;Reinhard, Christian;Santoni, Federico A.;Uchil, Pradeep D.;Chatel, Laurence;Bisiaux, Aurelie;Albert, Matthew L.;Strambio-De-Castillia, Caterina;Mothes, Walther;Pizzato, Massimo;Gruetter, Markus G.;Luban, Jeremy
通讯作者：
Luban, Jeremy