Biochemical and genetic characterizations of a novel human immunodeficiency virus type 1 inhibitor that blocks gp120-CD4 interactions
Biochemical and genetic characterizations of a novel human immunodeficiency virus type 1 inhibitor that blocks gp120-CD4 interactions
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DOI：
10.1128/jvi.77.19.10528-10536.2003
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发表时间：
2003-10-01
影响因子：
5.4
通讯作者：
Lin, PF
中科院分区：
文献类型：
--
作者：
Guo, Q;Ho, HT;Lin, PF
BMS-378806是最近发现的一种小分子人免疫缺陷病毒I型（HIV-1）附着抑制剂，具有良好的抗病毒活性和药代动力学特性。在这里，我们证明了该化合物的目标是通过抑制HIV-1包膜gp 120蛋白与细胞CD 4受体的结合，通过特异性和竞争性机制的病毒进入。BMS-378806以约1：1的化学计量直接与gp 120结合，结合亲和力与可溶性CD 4相似。通过使用携带化合物选择性耐药取代或gp 120-CD 4接触位点突变的HIV-1 gp 120变体，将潜在BMS-378806靶位点定位于gp 120的CD 4结合口袋内的特定区域。对HIV-1包膜的抗性取代的作图，以及对CD 4非依赖性病毒感染的化合物活性的缺乏，证实了gp 120-CD 4相互作用是感染细胞中的靶标。因此，BMS-378806可作为这类新型抗逆转录病毒药物的原型，并验证gp 120作为小分子抑制剂的可行靶点。
BMS-378806 is a recently discovered small-molecule human immunodeficiency virus type I (HIV-1) attachment inhibitor with good antiviral activity and pharmacokinetic properties. Here, we demonstrate that the compound targets viral entry by inhibiting the binding of the HIV-1 envelope gp120 protein to cellular CD4 receptors via a specific and competitive mechanism. BMS-378806 binds directly to gp120 at a stoichiometry of approximately 1:1, with a binding affinity similar to that of soluble CD4. The potential BMS-378806 target site was localized to a specific region within the CD4 binding pocket of gp120 by using HIV-1 gp120 variants carrying either compound-selected resistant substitutions or gp120-CD4 contact site mutations. Mapping of resistance substitutions to the HIV-1 envelope, and the lack of compound activity against a CD4-independent viral infection confirm the gp120-CD4 interactions as the target in infected cells. BMS-378806 therefore serves as a prototype for this new class of antiretroviral agents and validates gp120 as a viable target for small-molecule inhibitors.