Design of Plasmodium vivax Hypoxanthine-Guanine Phosphoribosyltransferase Inhibitors as Potential Antimalarial Therapeutics
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Antimalarials chemistry pharmacology MeSH
- Diphosphonates chemistry pharmacology MeSH
- Hypoxanthine Phosphoribosyltransferase antagonists & inhibitors chemistry metabolism MeSH
- Catalytic Domain MeSH
- Protein Conformation MeSH
- Crystallography, X-Ray MeSH
- Humans MeSH
- Models, Molecular MeSH
- Pentosyltransferases antagonists & inhibitors chemistry metabolism MeSH
- Plasmodium vivax enzymology MeSH
- Escherichia coli Proteins chemistry MeSH
- Drug Design MeSH
- Chemistry Techniques, Synthetic MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antimalarials MeSH
- Diphosphonates MeSH
- hypoxanthine-guanine-xanthine phosphoribosyltransferase MeSH Browser
- Hypoxanthine Phosphoribosyltransferase MeSH
- Pentosyltransferases MeSH
- Escherichia coli Proteins MeSH
Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the foremost causative agents of malaria. Due to the development of resistance to current antimalarial medications, new drugs for this parasitic disease need to be discovered. The activity of hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase, HG[X]PRT, is reported to be essential for the growth of both of these parasites, making it an excellent target for antimalarial drug discovery. Here, we have used rational structure-based methods to design an inhibitor, [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine, of PvHGPRT and PfHGXPRT that has Ki values of 8 and 7 nM, respectively, for these two enzymes. The crystal structure of PvHGPRT in complex with this compound has been determined to 2.85 Å resolution. The corresponding complex with human HGPRT was also obtained to allow a direct comparison of the binding modes of this compound with the two enzymes. The tetra-(ethyl l-phenylalanine) tetraamide prodrug of this compound was synthesized, and it has an IC50 of 11.7 ± 3.2 μM against Pf lines grown in culture and a CC50 in human A549 cell lines of 102 ± 11 μM, thus giving it a ∼10-fold selectivity index.
Centre for Advanced Imaging The University of Queensland St Lucia 4072 Australia
Department of Drug Evaluation Australian Army Malaria Institute Enoggera 4051 Australia
School of Chemistry and Molecular Biosciences The University of Queensland Brisbane 4072 Australia
References provided by Crossref.org
Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects
