Binding of anti-HIV drugs to human serum albumin
Binding of anti-HIV drugs to human serum albumin
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DOI：
10.1080/15216540400016286
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发表时间：
2004-10-01
期刊：
影响因子：
4.6
通讯作者：
Ascenzi, P
中科院分区：
文献类型：
--
作者：
Bocedi, A;Notaril, S;Ascenzi, P
人血清白蛋白 (HSA) 是血浆中最重要的蛋白质，以其卓越的配体（即药物）结合能力而闻名。此处，报告了 HIV 蛋白酶和逆转录酶抑制剂与 HSA 结合的解离平衡常数 (K-d) 值。阿巴卡韦、阿扎那韦、去羟肌苷、依非韦伦、恩曲他滨、拉米夫定、奈非那韦、奈韦拉平、利托那韦、沙奎那韦、司他夫定、扎西他滨和齐多夫定与位于子结构域 IIA 的 Sudlow 位点 I（即华法林裂口）的结合涉及改变 HSA 结构围绕 Trp214 并诱导内在色氨酸荧光猝灭。因此，主要与位于子结构域 IIIA 的 Sudlow 位点 II 结合的布洛芬不会影响 HSA 固有色氨酸荧光以及抗 HIV 药物与 Sudlow 位点 I 的结合。考虑到 HSA 的生理浓度（= 7.0 x 10(-4) M）、血浆中平均抗 HIV 药物浓度（= 1.0 x 10(-4) M），以及 抗HIV药物与HSA结合的K-d值（范围在4.4 x 10(-5) M和3.8 x 10(-4) M之间），看来HIV蛋白酶和逆转录酶抑制剂与HSA结合的比例在63%和91%之间。这代表了抗HIV治疗和管理中的一个显着缺陷，在血浆蛋白存在的情况下实现90%蛋白酶和逆转录酶抑制所需的抗HIV药物浓度似乎比不存在血浆蛋白时所需的浓度高至少一个数量级。
Human serum albumin (HSA), the most prominent protein in plasma, is best known for its exceptional ligand (i.e., drug) binding capacity. Here, values of the dissociation equilibrium constant (K-d) for the binding of HIV protease and reverse transcriptase inhibitors to HSA are reported. The binding of abacavir, atazanavir, didanosine, efavirenz, emtricitabine, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir, stavudine, zalcitabine, and zidovudine to the Sudlow site I (i.e., the warfarin cleft) located in the subdomain IIA involves the alteration of the HSA structure around Trp214 and induces intrinsic tryptophan fluorescence quenching. Accordingly, ibuprofen that primarily binds to the Sudlow site II located in the subdomain IIIA does not affect the HSA intrinsic tryptophan fluorescence and the binding of anti-HIV drugs to the Sudlow site I. Accounting for the physiological concentration of HSA (= 7.0 x 10(-4) M), the average anti-HIV drug concentration in plasma (= 1.0 x 10(-4) M), and K-d values for the binding of anti-HIV drugs to HSA ( ranging between 4.4 x 10(-5) M and 3.8 x 10(-4) M), it appears that the fraction of HIV protease and reverse transcriptase inhibitors bound to HSA ranges between 63% and 91%. This represents a significant drawback in the anti-HIV therapy and management, the anti-HIV drug concentration required to achieve 90% protease and reverse transcriptase inhibition in the presence of plasma proteins appears to be at least one order of magnitude higher than that required in their absence.