Biochemical and mechanistic basis for the activity of nucleoside analogue inhibitors of HIV reverse transcriptase.
Biochemical and mechanistic basis for the activity of nucleoside analogue inhibitors of HIV reverse transcriptase.
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HIV逆转录酶核苷类似物抑制剂活性的生化和机制基础。
DOI：
10.2174/1568026043388358
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发表时间：
2004
影响因子：
3.4
通讯作者：
D. Liotta
中科院分区：
文献类型：
--
作者：
G. Painter;M. Almond;Shuli Mao;D. Liotta
HIV编码一种RNA导向的DNA聚合酶（逆转录酶，RT），这是病毒复制周期中必不可少的酶。该酶通过双反应物-双产物机制催化单链基因组RNA合成双链前病毒DNA。从病毒颗粒中纯化的功能酶是由分子量分别为66,000和51,000的两个多肽组成的复合物。目前批准的四类抗hiv药物中的两类，核苷类逆转录酶抑制剂（NRTIs）和非核苷类逆转录酶抑制剂（NNRTIs），通过抑制这种酶起作用。本文介绍了nrti催化DNA合成的各个步骤，并详细介绍了nrti抑制DNA合成催化和终止的机制。利用瞬态动力学分析研究了催化循环中的各个步骤以及nrti对这些步骤的影响。综述了拉米夫定、coviracil和zalcitabine的立体异构体和抗性突变对NRTI三磷酸结合速率（k(pol)）、催化配合物结合速率（k(d)）和结合总效率(k（pol)/ k(d)）的影响。结果提供了洞察分子的力量和结构特征，使这些分子有效的抑制剂。
HIV encodes an RNA directed DNA polymerase (reverse transcriptase, RT) that is an essential enzyme in the viral replication cycle. This enzyme catalyzes the synthesis of double stranded proviral DNA from single stranded genomic RNA via a bireactant-biproduct mechanism. The functional enzyme purified from virus particles is a complex consisting of two polypeptides of molecular weight 66,000 and 51,000. Two of the four classes of currently approved anti-HIV drugs, the nucleoside reverse transcriptase inhibitors (NRTIs) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs), act by inhibiting this enzyme. In this review each step of DNA synthesis catalyzed by the RT is described and the mechanism of inhibition of catalysis and termination of DNA synthesis by NRTIs is detailed. The individual steps in the catalytic cycle and the effects that the NRTIs have on them have been examined using transient kinetic analysis. The impact of stereoisomerism and resistance mutations on the rate of NRTI triphosphate incorporation (k(pol)), binding in the catalytic complex (K(d)) and the overall efficiency of incorporation (k(pol)/K(d)) are summarized for lamivudine, coviracil and zalcitabine. The results provide insight into the molecular forces and structural features that make these molecules effective inhibitors.