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Acyclic nucleoside phosphonates containing a second phosphonate group are potent inhibitors of the 6-oxopurine phosphoribosyltransferases and have antimalarial activity

  • Dianne Keough1,
  • Petr Špaček2,
  • Dana Hocková2,
  • Tomáš Tichý2,
  • Silvie Vrbková2,
  • Lenka Slavětínská2,
  • Zlatko Janeba2,
  • Lieve Naesens3,
  • Michael Edstein4,
  • Marina Chavchich4,
  • Tzu Wang1,
  • John de Jersey1 and
  • Luke Guddat1
Malaria Journal201413(Suppl 1):P91

https://doi.org/10.1186/1475-2875-13-S1-P91

Published: 22 September 2014

Keywords

Crystal StructurePurineNucleosidePlasmodiumChemical Modification

Background

The 6-oxopurine phosphoribosyltransferases have been suggested to be a target for the discovery of new antimalarial drugs. This is because protozoan parasites rely solely on the salvage of purines from their host to make the nucleotides needed for RNA and DNA synthesis and lack the de novo pathway. Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) 6-oxopurine phosphoribosyltransferases (PRTs) [1]. Chemical modifications based on the crystal structure of 2-(phosphonoethoxy) ethylguanine (PEEG) in complex with human HGPRT have led to the design of new ANPs [2]. These novel compounds contain a second phosphonate group attached to the ANP scaffold [3].

Results

{[(2-[(Guanine-9Hyl)methyl]propane-1,3-diyl)bis(oxy)]bis (me thy-lene)} diphosphonic acid exhibited a Ki value of 30 nM for human HGPRT and 70 nM for Pf HGXPRT. The crystal structure of this compound in complex with human HGPRT shows that it fills or partially fills three critical locations in the active site: the binding sites of the purine base, the 5’-phosphate group, and pyrophosphate [3]. This is the first HG(X) PRT inhibitor that has been able to achieve this result. Pro-drugs have been synthesized resulting in IC50 values as low as 3.8 μM for Pf grown in cell culture, which is up to 25-fold lower compared to the parent compounds [3].

Conclusion

The crystal structure of {[(2-[(Guanine-9Hyl)methyl] propane-1,3-diyl)bis(oxy)]bis(methylene)} diphosphonic acid in complex with human HGPRT provides a template for chemical modifications to increase both potency and selectivity for the parasite enzymes.

Declarations

Acknowledgements

This work was financially supported by Australia National Health and Medical Research Council (Grants 569703 and 1030353), the Grant Agency of Czech Republic (Grant P207/11/0108) and Gilead Sciences (Foster city, CA).

Authors’ Affiliations

(1)
School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia
(2)
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
(3)
Rega Institue for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium
(4)
Australia Army Malaria Institute, Brisbane, Australia

References

  1. Hockova D, Holy A, Masojidkova M, Keough DT, de Jersey J, Guddat LW: Synthesis of branched 9-[2-(2-phosphonoethoxy)ethyl]purines as a new class of acyclic nucleoside phosphonates which inhibit Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase. Bioorg Med Chem. 2009, 17: 6218-6232. 10.1016/j.bmc.2009.07.044.View ArticlePubMedGoogle Scholar
  2. Keough DT, Hockova D, Holy A, Naesens LM, Skinner-Adams TS, Jersey J, Guddat LW: Inhibition of hypoxanthine-guanine phosphoribosyltransferase by acyclic nucleoside phosphonates: a new class of antimalarial therapeutics. J Med Chem. 2009, 52: 4391-4399. 10.1021/jm900267n.View ArticlePubMedGoogle Scholar
  3. Keough DT, Spacek P, Hockova D: Acyclic nucleoside phosphonates containing a second phosphonate group are potent inhibitors of 6-oxopurine phosphoribosyltransferases and have antimalarial activity. J Med Chem. 2013, 56: 2513-2526. 10.1021/jm301893b.View ArticlePubMedGoogle Scholar

Copyright

© Keough et al; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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