Inhibition of HIV-1 envelope-mediated fusion by synthetic batzelladine analogues
Inhibition of HIV-1 envelope-mediated fusion by synthetic batzelladine analogues
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DOI：
10.1021/np049958o
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发表时间：
2004-08-01
影响因子：
5.1
通讯作者：
Overman, LE
中科院分区：
文献类型：
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作者：
Bewley, CA;Ray, S;Overman, LE
以多环胍基序为特征的海洋天然产物，如克兰贝西汀和巴泽拉定，已知对包括HSV和HIV在内的一些病毒具有抗病毒活性。在这项研究中，我们评估了一个包含28个巴齐拉定类似物的合成文库，其结构包含并超过了天然巴齐拉定的变化，因为它们能够抑制HIV-1包膜介导的细胞-细胞融合。结果表明，最佳融合抑制剂的结构与天然巴齐拉定F最相似，IC50值在0.8 ~ 3.0 ma之间。从早期发现一些巴齐拉定阻断gp120-CD4结合开始，我们对gp120上的CD4结合位点的抑制剂进行了建模研究。最低能量模型表明抑制剂结合的首选方向与观察到的结构-活性关系一致。
Marine natural products that feature polycyclic guanidine motifs, such as crambescidins and batzelladines, are known to have antiviral activities toward some viruses including HSV and HIV. In this study we evaluated a synthetic library containing 28 batzelladine analogues, the structures of which encompass and surpass variations seen in natural batzelladines, for their ability to inhibit HIV-1 envelope-mediated cell-cell fusion. Clear structure-activity relationships were revealed and indicated that the best inhibitors of fusion were most similar in structure to natural batzelladine F, with IC50 values ranging from 0.8 to 3.0muM. Proceeding from the earlier finding that some batzelladines block gp120-CD4 binding, modeling studies of inhibitors binding to the CD4 binding site on gp120 were carried out. The lowest energy models suggest a preferred orientation for inhibitor binding that is consistent with the observed structure-activity relationships.