Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: a scaffold hopping approach using salicylate and catechol groups.
Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: a scaffold hopping approach using salicylate and catechol groups.
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DOI：
10.1016/j.bmc.2011.06.058
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发表时间：
2011-08-15
影响因子：
3.5
通讯作者：
Long, Ya-Qiu
中科院分区：
文献类型：
--
作者：
Fan, Xing;Zhang, Feng-Hua;Al-Safi, Rasha I.;Zeng, Li-Fan;Shabaik, Yumna;Debnath, Bikash;Sanchez, Tino W.;Odde, Srinivas;Neamati, Nouri;Long, Ya-Qiu
HIV-1整合酶（IN）是一种有效的抗病毒药物治疗靶点。然而，对临床研究的IN抑制剂耐药的病毒株的出现需要新的结构和新的IN抑制剂机制。在此，我们描述了新的IN抑制剂的设计和发现，靶向催化结构域以及其与LEDGF/p75的相互作用，这是必不可少的HIV-1整合作为IN辅因子。通过将水杨酸和邻苯二酚的药效团合并，2，3-二羟基苯甲酰胺（5a）被鉴定为有效抑制链转移反应的新支架。对2，3-二羟基苯甲酰胺骨架的进一步结构修饰表明，连接在羧酰胺部分上的杂芳族官能团和苯环上取代的哌啶-1-基磺酰基有利于活性，导致低微摩尔IN抑制剂（5 p，IC 50 = 5 μM），其对链转移的选择性超过3′-加工反应的40倍。更重要的是，这种活性支架显着抑制IN和LEDGF/p75辅因子之间的相互作用。原型实例N-（环己基甲基）-2，3-二羟基-5-（哌啶-1-基磺酰基）苯甲酰胺（5 u）抑制IN-LEDGF/p75相互作用，IC 50值为8 μM。基于分子模拟，假设作用机制涉及IN活性位点内二价金属离子的螯合。IN-LEDGF/p75相互作用抑制剂与IN蛋白的LEDGF/p75结合位点结合良好。本工作为从已有的HIV-1 IN抑制剂中合理整合和优化新的HIV-1 IN抑制剂提供了一条新的有效途径。
HIV-1 integrase (IN) is a validated therapeutic target for antiviral agents. However, the emergence of viral strains resistant to clinically studied IN inhibitors demands new structure and new mechanism IN inhibitors. Herein, we describe the design and discovery of novel IN inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75, which is essential for the HIV-1 integration as an IN cofactor. By merging the pharmacophores of salicylate and catechol, the 2,3-dihydroxybenzamide (5a) was identified as a new scaffold to inhibit the strand transfer reaction efficiently. Further structural modifications on the 2,3-dihydroxybenzamide scaffold revealed that the heteroaromatic functionality attached on the carboxamide portion and the piperidin-1-ylsulfonyl substituted at the phenyl ring are beneficial for the activity, resulting in a low micromolar IN inhibitor (5p, IC50 = 5 μM) with more than 40-fold selectivity for the strand transfer over the 3′-processing reaction. More significantly, this active scaffold remarkably inhibited the interaction between IN and LEDGF/p75 cofactor. The prototype example, N-(cyclohexylmethyl)-2,3-dihydroxy-5-(piperidin-1-ylsulfonyl) benzamide (5u) inhibited the IN-LEDGF/p75 interaction with an IC50 value of 8 μM. Based on the molecular modeling, the mechanism of action was hypothesized to involve the chelation of the divalent metal ions inside the IN active site. And the inhibitor of IN-LEDGF/p75 interaction was properly bound to the LEDGF/p75 binding site in IN protein. This work provided a new and efficient approach to evolve novel HIV-1 IN inhibitors from rational integration and optimization of previously reported inhibitors.
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影响因子：
6.7
作者：
Hombrouck A;De Rijck J;Hendrix J;Vandekerckhove L;Voet A;De Maeyer M;Witvrouw M;Engelborghs Y;Christ F;Gijsbers R;Debyser Z
通讯作者：
Debyser Z
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：
4
作者：
Himmel, Daniel M.;Sarafianos, Stefan G.;Arnold, Eddy
通讯作者：
Arnold, Eddy
影响因子：
2.7
作者：
Al-Mawsawi, Laith Q.;Dayam, Raveendra;Neamati, Nouri
通讯作者：
Neamati, Nouri
影响因子：
7.3
作者：
Halgren, TA;Murphy, RB;Banks, JL
通讯作者：
Banks, JL