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Molecular Pharmacology

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Research ArticleArticle

Role of Human Hypoxanthine Guanine Phosphoribosyltransferase in Activation of the Antiviral Agent T-705 (Favipiravir)

Lieve Naesens, Luke W. Guddat, Dianne T. Keough, André B. P. van Kuilenburg, Judith Meijer, Johan Vande Voorde and Jan Balzarini
Molecular Pharmacology October 2013, 84 (4) 615-629; DOI: https://doi.org/10.1124/mol.113.087247
Lieve Naesens
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium (L.N., J.V.V., J.B.); School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia (L.W.G., D.T.K.); and Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands (A.B.P.v.K., J.M.)
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Luke W. Guddat
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium (L.N., J.V.V., J.B.); School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia (L.W.G., D.T.K.); and Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands (A.B.P.v.K., J.M.)
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Dianne T. Keough
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium (L.N., J.V.V., J.B.); School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia (L.W.G., D.T.K.); and Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands (A.B.P.v.K., J.M.)
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André B. P. van Kuilenburg
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium (L.N., J.V.V., J.B.); School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia (L.W.G., D.T.K.); and Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands (A.B.P.v.K., J.M.)
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Judith Meijer
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium (L.N., J.V.V., J.B.); School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia (L.W.G., D.T.K.); and Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands (A.B.P.v.K., J.M.)
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Johan Vande Voorde
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium (L.N., J.V.V., J.B.); School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia (L.W.G., D.T.K.); and Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands (A.B.P.v.K., J.M.)
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Jan Balzarini
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium (L.N., J.V.V., J.B.); School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia (L.W.G., D.T.K.); and Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands (A.B.P.v.K., J.M.)
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Abstract

6-Fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) is a novel antiviral compound with broad activity against influenza virus and diverse RNA viruses. Its active metabolite, T-705-ribose-5′-triphosphate (T-705-RTP), is recognized by influenza virus RNA polymerase as a substrate competing with GTP, giving inhibition of viral RNA synthesis and lethal virus mutagenesis. Which enzymes perform the activation of T-705 is unknown. We here demonstrate that human hypoxanthine guanine phosphoribosyltransferase (HGPRT) converts T-705 into its ribose-5′-monophosphate (RMP) prior to formation of T-705-RTP. The anti-influenza virus activity of T-705 and T-1105 (3-hydroxy-2-pyrazinecarboxamide; the analog lacking the 6-fluoro atom) was lost in HGPRT-deficient Madin-Darby canine kidney cells. This HGPRT dependency was confirmed in human embryonic kidney 293T cells undergoing HGPRT-specific gene knockdown followed by influenza virus ribonucleoprotein reconstitution. Knockdown for adenine phosphoribosyltransferase (APRT) or nicotinamide phosphoribosyltransferase did not change the antiviral activity of T-705 and T-1105. Enzymatic assays showed that T-705 and T-1105 are poor substrates for human HGPRT having Kmapp values of 6.4 and 4.1 mM, respectively. Formation of the RMP metabolites by APRT was negligible, and so was the formation of the ribosylated metabolites by human purine nucleoside phosphorylase. Phosphoribosylation and antiviral activity of the 2-pyrazinecarboxamide derivatives was shown to require the presence of the 3-hydroxyl but not the 6-fluoro substituent. The crystal structure of T-705-RMP in complex with human HGPRT showed how this compound binds in the active site. Since conversion of T-705 by HGPRT appears to be inefficient, T-705-RMP prodrugs may be designed to increase the antiviral potency of this new antiviral agent.

Footnotes

    • Received May 11, 2013.
    • Accepted August 1, 2013.
  • This work was supported by a grant from the Geconcerteerde Onderzoeksacties [GOA/10/014] of KU Leuven; and funds from the National Health and Medical Research Council [Grant No. 1030353]. J.V.V. received a PhD grant from the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen).

  • dx.doi.org/10.1124/mol.113.087247.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (4)
Molecular Pharmacology
Vol. 84, Issue 4
1 Oct 2013
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Research ArticleArticle

Phosphoribosylation of T-705 by Human HGPRT

Lieve Naesens, Luke W. Guddat, Dianne T. Keough, André B. P. van Kuilenburg, Judith Meijer, Johan Vande Voorde and Jan Balzarini
Molecular Pharmacology October 1, 2013, 84 (4) 615-629; DOI: https://doi.org/10.1124/mol.113.087247

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Research ArticleArticle

Phosphoribosylation of T-705 by Human HGPRT

Lieve Naesens, Luke W. Guddat, Dianne T. Keough, André B. P. van Kuilenburg, Judith Meijer, Johan Vande Voorde and Jan Balzarini
Molecular Pharmacology October 1, 2013, 84 (4) 615-629; DOI: https://doi.org/10.1124/mol.113.087247
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