Thermodynamics of binding of a low-molecular-weight CD4 mimetic to HIV-1 gp120
Thermodynamics of binding of a low-molecular-weight CD4 mimetic to HIV-1 gp120
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DOI：
10.1021/bi061193r
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发表时间：
2006-09-12
期刊：
影响因子：
2.9
通讯作者：
Freire, Ernesto
中科院分区：
文献类型：
--
作者：
Schon, Arne;Madani, Navid;Freire, Ernesto
NBD-556和化学和结构相似的NBD-557是两种低分子化合物，据报道，它们可以阻断HIV-1包膜糖蛋白gp120及其受体CD4之间的相互作用。NBD-556以2.7×10(5)M-1(K-d=3.7µM)的结合亲和力与gp120结合，其特征是较大的有利热变被较大的不利熵变部分补偿，这一热力学特征类似于观察到的sCD4与gp120结合的热力学特征。正如CD光谱所证明的那样，NBD556结合与gp120分子的大结构有关。NBD-556和CD4一样，激活gp120与HIV-1辅助受体CCR5和识别gp120辅助受体结合位置的17b单抗的结合。NBD-556刺激CD4阴性、CCR5表达的细胞感染HIV-1。NBD556与gp120结合的热力学特征与另一种病毒进入抑制剂BMS-378806的热力学特征非常不同。虽然nbd556与gp120结合有较大的有利热焓，并补偿不利的熵变化，但bms-378806在主要由熵驱动的过程中结合有较小的结合热焓变化。NBD556是sCD_4的竞争性抑制剂，可以引起类似的辅受体结合部位的结构，而BMS-378806不与sCD_4竞争，也不诱导辅受体结合。这些研究表明，低分子化合物可以诱导HIV-1 gp120糖蛋白的构象变化，类似于CD4结合时观察到的变化，揭示了抑制HIV-1 gp120包膜糖蛋白功能的不同策略。此外，竞争性和非竞争性化合物具有独特的热力学特征，可用于指导设计更有效和更有效的病毒进入抑制剂。
NBD-556 and the chemically and structurally similar NBD-557 are two low-molecular weight compounds that reportedly block the interaction between the HIV-1 envelope glycoprotein gp120 and its receptor, CD4. NBD-556 binds to gp120 with a binding affinity of 2.7 x 10(5) M-1 ( K-d = 3.7 mu M) in a process characterized by a large favorable change in enthalpy partially compensated by a large unfavorable entropy change, a thermodynamic signature similar to that observed for binding of sCD4 to gp120. NBD556 binding is associated with a large structuring of the gp120 molecule, as also demonstrated by CD spectroscopy. NBD-556, like CD4, activates the binding of gp120 to the HIV-1 coreceptor, CCR5, and to the 17b monoclonal antibody, which recognizes the coreceptor binding site of gp120. NBD-556 stimulates HIV-1 infection of CD4-negative, CCR5-expressing cells. The thermodynamic signature of the binding of NBD- 556 to gp120 is very different from that of another viral entry inhibitor, BMS-378806. Whereas NBD- 556 binds gp120 with a large favorable enthalpy and compensating unfavorable entropy changes, BMS-378806 does so with a small binding enthalpy change in a mostly entropy-driven process. NBD556 is a competitive inhibitor of sCD4 and elicits a similar structuring of the coreceptor binding site, whereas BMS-378806 does not compete with sCD4 and does not induce coreceptor binding. These studies demonstrate that low-molecular-weight compounds can induce conformational changes in the HIV-1 gp120 glycoprotein similar to those observed upon CD4 binding, revealing distinct strategies for inhibiting the function of the HIV-1 gp120 envelope glycoprotein. Furthermore, competitive and noncompetitive compounds have characteristic thermodynamic signatures that can be used to guide the design of more potent and effective viral entry inhibitors.