新药物疗法对抗HIV病毒将取代传统鸡尾酒疗法

生物谷

    生物谷：来自Minnesota大学药物研发中心的科学家最近发明了一种新的对抗HIV/艾滋病的方法，这或许能在将来取代目前使用的传统鸡尾酒疗法。

    新方法已经在实验室测试中被证明是有效的，它将两种抗病毒药物结合到一起，从而实现了和两种或多种药物分别起作用时完全相同的效果。传统鸡尾酒疗法通常是针对那些HIV感染病人，这种方法昂贵且毒性很高，因为它需要多种药物同时起作用。

    科学家将此次发现的新方法命名为Portmanteau  Inhibitor，他们将研究结果发表在Journal  of  Medicinal  Chemistry上。主要负责科学家是Robert  Vince博士，他同时还是药学院药物化学教授以及中心的主任。

    Vince表示：“这是用一种药物起到两种药物分别作用时的效果。它是全新的HIV/AIDS治疗方法。”除了没有价格昂贵和高毒性问题，这一方法还比较难发展出病毒的抗药性。最重要的是，科学家们发现药物的各个不同组分之间在攻击HIV时不会互相干扰。

    来自药物研发中心的Zhenqiang  Wang博士是项目成员之一，他认为：“单独一种药物无法持久起作用，因为它能很快带来抗药性。因此新方法使得抗药性很难形成。”

    下一步科学家将进行更多研究来分析药物分布于体内时如何起作用。但是Wang表示，初期实验已近有很好的效果，因为艾滋病人的生活质量得到了提高，而且他们的花费和毒副作用都较小。Wang说：“这一新的概念将取代传统的鸡尾酒疗法。”（教育部科技发展中心）

原始出处:

J. Med. Chem., 50 (15), 3416 -3419, 2007. 10.1021/jm070512p S0022-2623(07)00512-2
Web Release Date: July 4, 2007 Copyright © 2007 American Chemical Society

Rationally Designed Dual Inhibitors of HIV Reverse Transcriptase and Integrase

Zhengqiang Wang, Eric M. Bennett, Daniel J. Wilson, Christine Salomon, and Robert Vince*

Center for Drug Design, Academic Health Center, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455

Received May 2, 2007

Abstract:

Bifunctional inhibitors were designed and synthesized based on 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)a1 non-nucleoside reverse transcriptase (RT) inhibitors and diketoacid (DKA) integrase (IN) inhibitors. Biochemical studies revealed activity against RT and IN at low nanomolar and low micromolar concentrations, respectively. Exceptionally low IC50 values from a cell-based assay were achieved along with remarkably high therapeutic indices. Compound 7 was identified as the best compound of the series (IC50: 24 nM against RT, 4.4 M against IN, and 10 nM against HIV-1).

Figure 1 Structures of reported compounds active against RT and IN.

Morphy and Rankovic18 reviewed designed multifunctional ligands and proposed nomenclature based on whether the scaffolds were combined by a linker (a "conjugate"), directly coupled with no linker ("fused"), or integrated into a single scaffold sharing common features ("merged"). However, classification based on the targeted binding sites is also possible. For example, the sites may (a) be adjacent pockets of a single protein,20,21 (b) be located on different proteins but recognize similar endogenous ligands,22,23 or (c) be located on different proteins and recognize dissimilar or no endogenous ligands.24-26 We propose the term portmanteau inhibitor27 to define what is arguably the most challenging design problem under these classifications: two scaffolds merged into one scaffold, which binds multiple sites that do not recognize similar endogenous ligands. The classification based on the types of binding sites differs from that of Morphy and Rankovic, which is based solely on the ligand structure. Here, we report a series of these inhibitors (Figure 2) targeting IN and the non-nucleoside RT site. The compounds show activity against live virus and have low cytotoxicity.

全文链接：http://pubs.acs.org/cgi-bin/article.cgi/jmcmar/2007/50/i15/html/jm070512p.html

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