Defining a molecular mechanism of synergy between nucleoside and nonnucleoside AIDS drugs
Defining a molecular mechanism of synergy between nucleoside and nonnucleoside AIDS drugs
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DOI：
10.1074/jbc.c300523200
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发表时间：
2004-02-20
影响因子：
4.8
通讯作者：
Anderson, KS
中科院分区：
文献类型：
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作者：
Basavapathruni, A;Bailey, CM;Anderson, KS
治疗人类免疫缺陷病毒1型（HIV-1）感染的联合疗法可延迟耐药病毒的出现，并表现出协同抑制作用。这种协同作用在靶向基本病毒逆转录酶（RT）的两类抑制剂中观察到：链终止核苷类似物（NRTI）和在不同于活性位点的口袋中结合的变构非核苷（NNR-Tis）。定义这两类之间协同作用的分子基础的一般机制仍有待阐明。我们实验室以前的机理研究（Spence，R.一、Kati，W. M.，安德森，K.美国，和约翰逊，K. A.（1995）Science 267，988-993）已经表明天然脱氧核苷三磷酸和NNRTI可以同时结合到它们各自的位点。这项工作也表明这两个网站之间的通信，因为抑制RT的NNRTI是通过对化学步骤的远程影响。这两个网站之间的相互作用提供了一个合理的假设，了解协同作用，其中结合NNRTI调制链终止NRTI。本研究通过说明临床批准的NNRTI、奈韦拉平和依法韦仑抑制ATP介导的AZTMP、d4 TMP、ddCMP、（-）3 TCMP、（-）FTCMP和（+）3 TCMP的清除，从而延长链终止的有效性，支持了这一假设。这种抑制是通过对化学步骤的速率和ATP结合的影响介导的，导致去除效率的总体降低。这项工作证实了两个结合口袋之间的通信，持续使用联合治疗来治疗HIV感染，以及理解协同作用的分子基础。
Combination therapies treating human immunodeficiency virus type 1 (HIV-1) infection delay the emergence of drug-resistant virus and exhibit synergistic inhibition. This synergy is observed within the two classes of inhibitors that target the essential viral reverse transcriptase (RT): the chain-terminating nucleoside analogs (NRTIs) and the allosteric nonnucleosides (NNR-Tis) that bind in a pocket distinct from the active site. A general mechanism to define the molecular basis for synergy between these two classes remains to be elucidated. Previous mechanistic studies from our laboratory (Spence, R. A., Kati, W. M., Anderson, K. S., and Johnson, K. A. (1995) Science 267, 988-993) have shown that the natural deoxynucleoside triphosphate and the NNRTI can simultaneously bind to their respective sites. This work also suggests communication between the two sites, since the inhibition of RT by NNRTIs is manifested through a remote effect on the chemical step. This interplay between the two sites offers a plausible hypothesis for understanding synergy in which binding of NNRTIs modulates the chain termination by NRTIs. The present study supports this hypothesis by illustrating that the clinically approved NNRTIs, nevirapine and efavirenz, inhibit the ATP-mediated removal of AZTMP, d4TMP, ddCMP, (-)3TCMP, (-)FTCMP, and (+)3TCMP, thereby prolonging the effectiveness of chain termination. This inhibition is mediated through an effect on both the rate of the chemical step and binding of ATP, resulting in an overall decrease in efficiency of removal. This work substantiates communication between the two binding pockets, the sustained use of combination therapy to treat HIV infection, and a molecular basis for understanding synergy.