生物谷：來自Minnesota大學(xué)藥物研發(fā)中心的科學(xué)家最近發(fā)明了一種新的對抗HIV/艾滋病的方法,，這或許能在將來取代目前使用的傳統(tǒng)雞尾酒療法,。
新方法已經(jīng)在實驗室測試中被證明是有效的，它將兩種抗病毒藥物結(jié)合到一起,，從而實現(xiàn)了和兩種或多種藥物分別起作用時完全相同的效果,。傳統(tǒng)雞尾酒療法通常是針對那些HIV感染病人，這種方法昂貴且毒性很高,，因為它需要多種藥物同時起作用,。
科學(xué)家將此次發(fā)現(xiàn)的新方法命名為Portmanteau Inhibitor，他們將研究結(jié)果發(fā)表在Journal of Medicinal Chemistry上,。主要負(fù)責(zé)科學(xué)家是Robert Vince博士,，他同時還是藥學(xué)院藥物化學(xué)教授以及中心的主任。
Vince表示：“這是用一種藥物起到兩種藥物分別作用時的效果,。它是全新的HIV/AIDS治療方法,。”除了沒有價格昂貴和高毒性問題，這一方法還比較難發(fā)展出病毒的抗藥性,。最重要的是,，科學(xué)家們發(fā)現(xiàn)藥物的各個不同組分之間在攻擊HIV時不會互相干擾。
來自藥物研發(fā)中心的Zhenqiang Wang博士是項目成員之一,，他認(rèn)為：“單獨一種藥物無法持久起作用,，因為它能很快帶來抗藥性。因此新方法使得抗藥性很難形成,。”
下一步科學(xué)家將進行更多研究來分析藥物分布于體內(nèi)時如何起作用,。但是Wang表示，初期實驗已近有很好的效果，因為艾滋病人的生活質(zhì)量得到了提高,，而且他們的花費和毒副作用都較小,。Wang說：“這一新的概念將取代傳統(tǒng)的雞尾酒療法。”（教育部科技發(fā)展中心）
原始出處:
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.
全文鏈接：http://pubs.acs.org/cgi-bin/article.cgi/jmcmar/2007/50/i15/html/jm070512p.html
