Investigation of the molecular characteristics of bisindole inhibitors as HIV-1 glycoprotein-41 fusion inhibitors.
Investigation of the molecular characteristics of bisindole inhibitors as HIV-1 glycoprotein-41 fusion inhibitors.
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DOI：
10.1016/j.ejmech.2018.10.048
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发表时间：
2019-01-01
影响因子：
6.7
通讯作者：
Gochin M
中科院分区：
文献类型：
--
作者：
Zhou G;Chu S;Nemati A;Huang C;Snyder BA;Ptak RG;Gochin M
在先前的工作中，我们描述了靶向病毒糖蛋白-41的N-七肽重复区上的疏水口袋的6- 6 '-双吲哚化合物作为HIV-1融合的有效抑制剂。具有亚微摩尔IC 50的两种有前途的化合物含有在两个吲哚氮上连接的苯甲酸基团和苯甲酸酯。在这里，我们进行了全面的SAR研究，评价每个环系统和各种取代基对化合物效力的贡献。改变疏水性、极性和电荷以产生35种新化合物，在结合、细胞-细胞融合和病毒感染性测定中对所述化合物进行评价。我们发现，（a）仅基于增加疏水含量的活性在约200 nM处达到稳定;（B）双吲哚支架的功效超过其他杂环系统;（c）口袋中可能涉及Gln 575的极性相互作用可以取代特异性较低的疏水相互作用;以及（d）苯甲酸酯部分似乎未与口袋形成特异性接触。这种疏水基团对化合物效力的重要性表明了一种机制，即它可能在融合过程中与第三组分（如膜）相互作用。发现了一种具有亚μM活性的有前途的小分子10 b，其分子量< 500 da，与早期化合物相比降低了logP。这项工作为小分子抑制HIV-1融合的要求提供了深入了解。
In previous work, we described 6–6’-bisindole compounds targeting a hydrophobic pocket on the N-heptad repeat region of viral glycoprotein-41 as effective inhibitors of HIV-1 fusion. Two promising compounds with sub-micromolar IC50’s contained a benzoic acid group and a benzoic acid ester attached at the two indole nitrogens. Here we have conducted a thorough SAR study evaluating the contribution of each of the ring systems and various substituents to compound potency. Hydrophobicity, polarity and charge were varied to produce 35 new compounds that were evaluated in binding, cell-cell fusion and viral infectivity assays. We found that (a) activity based solely on increasing hydrophobic content plateaued at ~ 200 nM; (b) the bisindole scaffold surpassed other heterocyclic ring systems in efficacy; (c) a polar interaction possibly involving Gln575 in the pocket could supplant less specific hydrophobic interactions; and (d) the benzoic acid ester moiety did not appear to form specific contacts with the pocket. The importance of this hydrophobic group to compound potency suggests a mechanism whereby it might interact with a tertiary component during fusion, such as membrane. A promising small molecule 10b with sub-μM activity was discovered with molecular weight < 500 da and reduced logP compared to earlier compounds. The work provides insight into requirements for small molecule inhibition of HIV-1 fusion.
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影响因子：
120.1
作者：
Leeson, Paul D.;Springthorpe, Brian
通讯作者：
Springthorpe, Brian
影响因子：
7.3
作者：
Gillis, Eric P.;Eastman, Kyle J.;Meanwell, Nicholas A.
通讯作者：
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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
影响因子：
7.3
作者：
Zhou G;Sofiyev V;Kaur H;Snyder BA;Mankowski MK;Hogan PA;Ptak RG;Gochin M
通讯作者：
Gochin M
影响因子：
2.9
作者：
Strockbine, Bentley;Rizzo, Robert C.
通讯作者：
Rizzo, Robert C.