Design, synthesis, and biological evaluation of N-carboxyphenylpyrrole derivatives as potent HIV fusion inhibitors targeting gp41.
Design, synthesis, and biological evaluation of N-carboxyphenylpyrrole derivatives as potent HIV fusion inhibitors targeting gp41.
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作为针对 gp41 的有效 HIV 融合抑制剂的 N-羧基苯基吡咯衍生物的设计、合成和生物学评价。
DOI：
10.1021/jm800869t
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发表时间：
2008-12-25
影响因子：
7.3
通讯作者：
Xie L
中科院分区：
文献类型：
--
作者：
Liu K;Lu H;Hou L;Qi Z;Teixeira C;Barbault F;Fan BT;Liu S;Jiang S;Xie L
基于HIV-1 gp 41靶向小分子靶向化合物N-（4-羧基-3-羟基）苯基-2，5-二甲基吡咯（2，NB-2）和N-（3-羧基-4-氯）苯基吡咯（A1，NB-64）的结构，设计合成了A和B两大类42个N-羧基苯基吡咯衍生物。我们发现11个化合物在微摩尔水平上表现出有希望的抗HIV-1活性，并且它们的抗病毒活性与它们对gp 41六螺旋束形成的抑制活性相关，这表明这些化合物通过破坏gp 41核心形成来阻断HIV融合和进入。构效关系和分子对接分析表明，羧基可以与Arg 579或Lys 574形成盐桥，吡咯环上的两个甲基有利于与gp 41口袋中的残基相互作用。活性最高的化合物N-（3-羧基-4-羟基）苯基-2，5-二甲基吡咯（A12）部分占据了深疏水口袋，表明增大A12的分子尺寸可以提高其结合亲和力和抗HIV-1活性，从而进一步开发为小分子HIV融合和进入抑制剂。
Based on the structures of small-molecule hits targeting the HIV-1 gp41, N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole (2, NB-2) and N-(3-carboxy-4-chloro)phenylpyrrole (A1, NB-64), 42 N-carboxyphenylpyrrole derivatives in two categories (A and B series) were designed and synthesized. We found that 11 compounds exhibited promising anti-HIV-1 activity at micromolar level and their antiviral activity was correlated with their inhibitory activity on gp41 six-helix bundle formation, suggesting that these compounds block HIV fusion and entry by disrupting gp41 core formation. The structure-activity relationship and molecular docking analysis revealed that the carboxyl group could interact with either Arg579 or Lys574 to form salt bridges and two methyl groups on the pyrrole ring were favorable for interaction with the residues in gp41 pocket. The most active compound, N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrrole (A12), partially occupied the deep hydrophobic pocket, suggesting that enlarging the molecular size of A12 could improve its binding affinity and anti-HIV-1 activity for further development as a small-molecule HIV fusion and entry inhibitor.
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影响因子：
7.3
作者：
Debnath, AK;Radigan, L;Jiang, SB
通讯作者：
Jiang, SB
影响因子：
3.8
作者：
Richman, DD;Morton, SC;Bozzette, SA
通讯作者：
Bozzette, SA
影响因子：
--
作者：
Liu, SW;Boyer-Chatenet, L;Jiang, SB
通讯作者：
Jiang, SB
影响因子：
3.1
作者：
Jiang, SB;Lin, K;Debnath, AK
通讯作者：
Debnath, AK
DOI：
10.1073/pnas.95.26.15613
发表时间：
1998-12-22
影响因子：
11.1
作者：
Chan, DC;Chutkowski, CT;Kim, PS
通讯作者：
Kim, PS