Betulinic acid derivatives that target gp120 and inhibit multiple genetic subtypes of human immunodeficiency virus type 1
Betulinic acid derivatives that target gp120 and inhibit multiple genetic subtypes of human immunodeficiency virus type 1
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DOI：
10.1128/aac.00737-07
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发表时间：
2008-01-01
影响因子：
4.9
通讯作者：
Chen, Chin-Ho
中科院分区：
文献类型：
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作者：
Lai, Weihong;Huang, Li;Chen, Chin-Ho
白桦酸(BA)衍生物可以抑制人类免疫缺陷病毒1型(HIV-1)的侵入或成熟，这依赖于侧链的修饰。尽管具有抗饱和活性的BA衍生物已经引起了人们的极大兴趣，但具有抗HIV-1进入活性的BA衍生物(称为BA进入抑制剂)的抗HIV-1谱和分子机制还没有很好的定义。在这项研究中，我们发现两个BA进入抑制剂IC9564和A43D显示出广泛的抗HIV-1活性。这两个化合物在亚微摩尔浓度下对来自A、B和C分支的多种HIV-1菌株具有抑制作用。C分支病毒对这些化合物的敏感性高于A和B分支病毒。有趣的是，IC9564在亚抑制浓度下可以改变其他进入抑制剂的抗融合活性。IC9564在增加HIV-1(YU2)Env介导的膜融合对CCR5抑制剂TAK-779的敏感性方面尤其有效。本研究结果表明，gp120的V3环是IC9564抗HIV-1活性的关键决定因素。IC9564逃逸病毒在V3环末端附近含有突变。IC9564与V3单抗447-52d和39f的结合具有竞争性。IC9564还与gp120/CD4复合体与趋化因子受体的结合竞争。综上所述，这些结果表明BA进入抑制剂可以通过靶向gp120的V3环而有效地抑制一系列主要的HIV-1分离株。
Betulinic acid (BA) derivatives can inhibit human immunodeficiency virus type 1 (HIV-1) entry or maturation depending on side chain modifications. While BA derivatives with antimaturation activity have attracted considerable interest, the anti-HIV-1 profile and molecular mechanism of BA derivatives with anti-HIV-1 entry activity (termed BA entry inhibitors) have not been well defined. In this study, we have found that two BA entry inhibitors, IC9564 and A43D, exhibited a broad spectrum of anti-HIV-1 activity. Both compounds inhibited multiple strains of HIV-1 from clades A, B, and C at submicromolar concentrations. Clade C viruses were more sensitive to the compounds than clade A and B viruses. Interestingly, IC9564 at subinhibitory concentrations could alter the antifusion activities of other entry inhibitors. IC9564 was especially potent in increasing the sensitivity of HIV-1(YU2) Env-mediated membrane fusion to the CCR5 inhibitor TAK-779. Results from this study suggest that the V3 loop of gp120 is a critical determinant for the anti-HIV-1 activity of IC9564. IC9564 escape viruses contained mutations near the tip of the V3 loop. Moreover, IC9564 could compete with the binding of V3 monoclonal antibodies 447-52D and 39F. IC9564 also competed with the binding of gp120/CD4 complexes to chemokine receptors. In summary, these results suggest that BA entry inhibitors can potently inhibit a broad spectrum of primary HIV-1 isolates by targeting the V3 loop of gp120.