从小隐孢子虫和刚地弓形虫中发现钙依赖性蛋白激酶1（CDPK1）的强效和选择性抑制剂
Discovery of Potent and Selective Inhibitors of Calcium-Dependent Protein Kinase 1 (CDPK1) from C. parvum and T. gondii.
作者信息
Murphy Ryan C, Ojo Kayode K, Larson Eric T, Castellanos-Gonzalez Alejandro, Perera B Gayani K, Keyloun Katelyn R, Kim Jessica E, Bhandari Janhavi G, Muller Natascha R, Verlinde Christophe L M J, White A Clinton, Merritt Ethan A, Van Voorhis Wesley C, Maly Dustin J
机构信息
Department of Chemistry, University of Washington.
出版信息
ACS Med Chem Lett. 2010 Oct 14;1(7):331-335. doi: 10.1021/ml100096t.
Abstract
The protozoans Cryptosporidium parvum and Toxoplasma gondii are parasites of major health concern to humans. Both parasites contain a group of calcium-dependent protein kinases (CDPKs), which are found in plants and ciliates but not in humans or fungi. Here we describe a series of potent inhibitors that target CDPK1 in C. parvum (CpCDPK1) and T. gondii (TgCDPK1). These inhibitors are highly selective for CpCDPK1 and TgCDPK1 over the mammalian kinases SRC and ABL. Furthermore, they are able to block an early stage of C. parvum invasion of HCT-8 host cells, which is similar to their effects on T. gondii invasion of human fibroblasts.
摘要
原生动物微小隐孢子虫和刚地弓形虫是对人类健康构成重大威胁的寄生虫。这两种寄生虫都含有一组钙依赖性蛋白激酶（CDPKs），这类激酶存在于植物和纤毛虫中，但在人类或真菌中不存在。在此，我们描述了一系列针对微小隐孢子虫（CpCDPK1）和刚地弓形虫（TgCDPK1）中CDPK1的强效抑制剂。这些抑制剂对CpCDPK1和TgCDPK1的选择性远高于哺乳动物激酶SRC和ABL。此外，它们能够阻断微小隐孢子虫入侵HCT - 8宿主细胞的早期阶段，这与它们对刚地弓形虫入侵人成纤维细胞的作用相似。
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本文引用的文献
1
Toxoplasma gondii calcium-dependent protein kinase 1 is a target for selective kinase inhibitors.
Nat Struct Mol Biol. 2010 May;17(5):602-7. doi: 10.1038/nsmb.1818. Epub 2010 May 2.
2
Use of the kinase inhibitor analog 1NM-PP1 reveals a role for Toxoplasma gondii CDPK1 in the invasion step.
Eukaryot Cell. 2010 Apr;9(4):667-70. doi: 10.1128/EC.00351-09. Epub 2010 Feb 19.
3
Calcium-dependent signaling and kinases in apicomplexan parasites.
Cell Host Microbe. 2009 Jun 18;5(6):612-22. doi: 10.1016/j.chom.2009.05.017.
4
Closing the diarrhoea diagnostic gap in Indian children by the application of molecular techniques.
J Med Microbiol. 2008 Nov;57(Pt 11):1364-1368. doi: 10.1099/jmm.0.2008/003319-0.
5
Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors.
J Med Chem. 2007 Feb 8;50(3):409-24. doi: 10.1021/jm0608107.
6
Cryptosporidium species: preliminary descriptions of the prevalence and genotype distribution among school children and hospital patients in the Venda region, Limpopo Province, South Africa.
Exp Parasitol. 2006 Dec;114(4):314-22. doi: 10.1016/j.exppara.2006.04.007. Epub 2006 Jun 27.
7
Comparative genomic and phylogenetic analyses of calcium ATPases and calcium-regulated proteins in the apicomplexa.
Mol Biol Evol. 2006 Aug;23(8):1613-27. doi: 10.1093/molbev/msl026. Epub 2006 Jun 2.
8
Protein kinases as targets for antimalarial intervention: Kinomics, structure-based design, transmission-blockade, and targeting host cell enzymes.
Biochim Biophys Acta. 2005 Dec 30;1754(1-2):132-50. doi: 10.1016/j.bbapap.2005.08.027. Epub 2005 Oct 6.
9
Structural bioinformatics-based design of selective, irreversible kinase inhibitors.
Science. 2005 May 27;308(5726):1318-21. doi: 10.1126/science1108367.
10
A second-site suppressor strategy for chemical genetic analysis of diverse protein kinases.
Nat Methods. 2005 Jun;2(6):435-41. doi: 10.1038/nmeth764.
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