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

Keough, Dianne T.; Špaček, Petr; Hocková, Dana; Tichý, Tomáš; Vrbková, Silvie; Slavětínská, Lenka Poštová; Janeba, Zlatko; Naesens, Lieve; Edstein, Michael D.; Chavchich, Marina; Wang, Tzu; Jersey, John de; Guddat, Luke W.

doi:10.1186/1475-2875-13-s1-p91

Cited by 16 publications

(57 citation statements)

References 3 publications

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“…6A). However, the usual p-stacking arrangement found when a purine base binds to human HGPRT is not observed here (Eads et al, 1994;Shi et al, 1999;Keough et al, 2009Keough et al, , 2013. This is a result of the carboxamide group in T-705 being more bulky than the 6-oxo group in the naturally occurring base substrates (Fig.…”

Section: Phosphoribosylation Of T-705 By Human Hgprtmentioning

confidence: 74%

“…The common feature of these structures is the absence of PP i or a mimic thereof. When the transition state analog immucillinGP binds along with PP i ×Mg 21 (Shi et al, 1999), or when {[(2-[(guanine-9H-yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)}diphosphonic acid binds (Keough et al, 2013), the side chain of Lys68 rotates away from the active site by 180°to allow PP i ×Mg 21 to enter. In the immucillinGP complex, the ribose is coordinated to Mg 21 and through this to PP i (Shi et al, 1999).…”

Section: Phosphoribosylation Of T-705 By Human Hgprtmentioning

confidence: 99%

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

et al. 2013

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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-59-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-59-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 K m app 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.

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Section: Phosphoribosylation Of T-705 By Human Hgprtmentioning

confidence: 74%

Section: Phosphoribosylation Of T-705 By Human Hgprtmentioning

confidence: 99%

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

et al. 2013

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“…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.…”

Section: Resultsmentioning

confidence: 84%

“…This is the first HG(X) PRT inhibitor that has been able to achieve this result. Pro-drugs have been synthesized resulting in IC 50 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].…”

Section: Resultsmentioning

confidence: 99%

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Acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group Are Potent Inhibitors of 6-Oxopurine Phosphoribosyltransferases and Have Antimalarial Activity

et al. 2013

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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). 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. These novel compounds contain a second phosphonate group attached to the ANP scaffold. {[(2-[(Guanine-9Hyl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)}diphosphonic acid (compound 17) exhibited a K i 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. This is the first HG(X)PRT inhibitor that has been able to achieve this result. Prodrugs have been synthesized resulting in IC 50 values as low as 3.8 μM for Pf grown in cell culture, up to 25-fold lower compared to the parent compounds.

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Medicinal Chemistry of Fluorinated Cyclic and Acyclic Nucleoside Phosphonates

Baszczyňski

Janeba

2013

Medicinal Research Reviews

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The fluorine atom plays an important role in medicinal chemistry because fluorine substitution has a strong impact on the physical, chemical, and biological properties of bioactive compounds. Such fluorine modifications have also been extensively studied among the pharmaceutically important class of nucleoside phosphonates, nucleotide analogues in which the phosphate group is replaced by the enzymatically and chemically stable phosphonate moiety. The fluorinated nucleoside phosphonates abound with antiviral, antiparasitic, and anticancer properties because they are able to act as inhibitors of important enzymes of nucleoside/nucleotide metabolism. In this paper, we review the biological properties of cyclic and acyclic nucleoside phosphonates modified by the attachment of one or more fluorine atoms to various parts of the molecule, namely to nucleobases, alkylphosphonate groups, cyclic or acyclic linkers, or to prodrug moieties.

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

Cited by 16 publications

References 3 publications

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

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

Acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group Are Potent Inhibitors of 6-Oxopurine Phosphoribosyltransferases and Have Antimalarial Activity

Medicinal Chemistry of Fluorinated Cyclic and Acyclic Nucleoside Phosphonates

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