Antiparasitic compounds that target DNA

被引:188
作者
Wilson, W. David [1 ]
Tanious, Farial A. [1 ]
Mathis, Amanda [2 ]
Tevis, Denise [1 ]
Hall, James Edwin [2 ]
Boykin, David W. [1 ]
机构
[1] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA
[2] Univ N Carolina, Sch Pharm, Div Drug Delivery & Disposit, Chapel Hill, NC 27599 USA
基金
美国国家卫生研究院;
关键词
antiparasitic drugs; heterocyclic diamidines; kinetoplast DNA; DNA topology; DNA binding;
D O I
10.1016/j.biochi.2008.02.017
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Designed, synthetic heterocyclic diamidines have excellent activity against eukaryotic parasites that cause diseases such as sleeping sickness and leishmania and adversely affect millions of people each year. The most active compounds bind specifically and strongly in the DNA minor groove at AT sequences. The compounds enter parasite cells rapidly and appear first in the kinetoplast that contains the mitochondrial DNA of the parasite. With time the compounds are also generally seen in the cell nucleus but are not significantly observed in the cytoplasm. The kinetoplast decays over time and disappears from the mitochondria of treated cells. At this point the compounds begin to be observed in other regions of the cell, such as the acidocalcisomes. The cells typically die in 24-48 h after treatment. Active compounds appear to selectively target extended AT sequences and induce changes in kinetoplast DNA minicircles that cause a synergistic destruction of the catenated kinetoplast DNA network and cell death. (c) 2008 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:999 / 1014
页数:16
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