期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 23, 期 7, 页码 2158-2161出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.01.097
关键词
Toxoplasma gondii; 1-Deoxy-D-xylulose-5-phosphate reductoisomerase; Protein expression; Enzyme inhibition; Structure-activity relationship
资金
- National Institute of Health (NIH) [R21AI088123, AI084415, AI64671, AI068467]
The apicomplexan parasite Toxoplasma gondii, the causative agent of toxoplasmosis, is an important human pathogen. 1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate isoprene biosynthesis pathway is essential to the organism and therefore a target for developing anti-toxoplasmosis drugs. In order to find potent inhibitors, we expressed and purified recombinant T. gondii DXR (TgDXR). Biochemical properties of this enzyme were characterized and an enzyme activity/inhibition assay was developed. A collection of 11 compounds with a broad structural diversity were tested against TgDXR and several potent inhibitors were identified with K-i values as low as 48 nM. Analysis of the results as well as those of Escherichia coli and Plasmodium falciparum DXR enzymes revealed a different structure-activity relationship profile for the inhibition of TgDXR. (C) 2013 Elsevier Ltd. All rights reserved.
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