Xanthine-based acyclic nucleoside phosphonates with potent antiviral activity against varicella-zoster virus and human cytomegalovirus
Identifieur interne : 000737 ( Ncbi/Merge ); précédent : 000736; suivant : 000738Xanthine-based acyclic nucleoside phosphonates with potent antiviral activity against varicella-zoster virus and human cytomegalovirus
Auteurs : Ond Ej Baszczy Ski [République tchèque] ; Martin Maxmilian Kaiser [République tchèque] ; Michal Esnek [République tchèque] ; Petra B Ehová [République tchèque] ; Petr Jansa [République tchèque] ; Eliška Procházková [République tchèque] ; Martin Dra Nsk [République tchèque] ; Robert Snoeck [Belgique] ; Graciela Andrei [Belgique] ; Zlatko Janeba [République tchèque]Source :
- Antiviral Chemistry & Chemotherapy [ 0956-3202 ] ; 2018.
Abstract
While noncanonic xanthine nucleotides XMP/dXMP play an important role in balancing and maintaining intracellular purine nucleotide pool as well as in potential mutagenesis, surprisingly, acyclic nucleoside phosphonates bearing a xanthine nucleobase have not been studied so far for their antiviral properties. Herein, we report the synthesis of a series of xanthine-based acyclic nucleoside phosphonates and evaluation of their activity against a wide range of DNA and RNA viruses. Two acyclic nucleoside phosphonates within the series, namely 9-[2-(phosphonomethoxy)ethyl]xanthine (PMEX) and 9-[3-hydroxy-2-(phosphonomethoxy)propyl]xanthine (HPMPX), were shown to possess activity against several human herpesviruses. The most potent compound was PMEX, a xanthine analogue of adefovir (PMEA). PMEX exhibited a single digit µM activity against VZV (EC50 = 2.6 µM, TK+ Oka strain) and HCMV (EC50 = 8.5 µM, Davis strain), while its hexadecyloxypropyl monoester derivative was active against HSV-1 and HSV-2 (EC50 values between 1.8 and 4.0 µM). In contrast to acyclovir, PMEX remained active against the TK– VZV 07–1 strain with EC50 = 4.58 µM. PMEX was suggested to act as an inhibitor of viral DNA polymerase and represents the first reported xanthine-based acyclic nucleoside phosphonate with potent antiviral properties.
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DOI: 10.1177/2040206618813050
PubMed: 30497281
PubMed Central: 6287304
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sortKey="Kaiser, Martin Maxmilian" sort="Kaiser, Martin Maxmilian" uniqKey="Kaiser M" first="Martin Maxmilian" last="Kaiser">Martin Maxmilian Kaiser</name><affiliation wicri:level="3"><nlm:aff id="aff1-2040206618813050">Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic</nlm:aff><country xml:lang="fr">République tchèque</country><wicri:regionArea>Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague</wicri:regionArea><placeName><settlement type="city">Prague</settlement><region type="région" nuts="2">Bohême centrale</region></placeName></affiliation></author><author><name sortKey=" Esnek, Michal" sort=" Esnek, Michal" uniqKey=" Esnek M" first="Michal" last=" Esnek">Michal Esnek</name><affiliation wicri:level="3"><nlm:aff id="aff1-2040206618813050">Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic</nlm:aff><country xml:lang="fr">République tchèque</country><wicri:regionArea>Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague</wicri:regionArea><placeName><settlement type="city">Prague</settlement><region type="région" nuts="2">Bohême centrale</region></placeName></affiliation></author><author><name sortKey="B Ehova, Petra" sort="B Ehova, Petra" uniqKey="B Ehova P" first="Petra" last="B Ehová">Petra B Ehová</name><affiliation wicri:level="3"><nlm:aff id="aff1-2040206618813050">Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic</nlm:aff><country xml:lang="fr">République tchèque</country><wicri:regionArea>Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague</wicri:regionArea><placeName><settlement type="city">Prague</settlement><region type="région" nuts="2">Bohême centrale</region></placeName></affiliation></author><author><name sortKey="Jansa, Petr" sort="Jansa, Petr" uniqKey="Jansa P" first="Petr" last="Jansa">Petr Jansa</name><affiliation wicri:level="3"><nlm:aff id="aff1-2040206618813050">Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic</nlm:aff><country xml:lang="fr">République tchèque</country><wicri:regionArea>Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague</wicri:regionArea><placeName><settlement type="city">Prague</settlement><region type="région" nuts="2">Bohême centrale</region></placeName></affiliation></author><author><name sortKey="Prochazkova, Eliska" sort="Prochazkova, Eliska" uniqKey="Prochazkova E" first="Eliška" last="Procházková">Eliška Procházková</name><affiliation wicri:level="3"><nlm:aff id="aff1-2040206618813050">Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic</nlm:aff><country xml:lang="fr">République tchèque</country><wicri:regionArea>Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague</wicri:regionArea><placeName><settlement type="city">Prague</settlement><region type="région" nuts="2">Bohême centrale</region></placeName></affiliation></author><author><name sortKey="Dra Nsk, Martin" sort="Dra Nsk, Martin" uniqKey="Dra Nsk M" first="Martin" last="Dra Nsk">Martin Dra Nsk</name><affiliation wicri:level="3"><nlm:aff id="aff1-2040206618813050">Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic</nlm:aff><country xml:lang="fr">République tchèque</country><wicri:regionArea>Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague</wicri:regionArea><placeName><settlement type="city">Prague</settlement><region type="région" nuts="2">Bohême centrale</region></placeName></affiliation></author><author><name sortKey="Snoeck, Robert" sort="Snoeck, Robert" uniqKey="Snoeck R" first="Robert" last="Snoeck">Robert Snoeck</name><affiliation wicri:level="1"><nlm:aff id="aff2-2040206618813050">Laboratory of Virology and Chemotheraphy, Rega Institute, Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Virology and Chemotheraphy, Rega Institute, Leuven</wicri:regionArea><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Andrei, Graciela" sort="Andrei, Graciela" uniqKey="Andrei G" first="Graciela" last="Andrei">Graciela Andrei</name><affiliation wicri:level="1"><nlm:aff id="aff2-2040206618813050">Laboratory of Virology and Chemotheraphy, Rega Institute, Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Virology and Chemotheraphy, Rega Institute, Leuven</wicri:regionArea><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Janeba, Zlatko" sort="Janeba, Zlatko" uniqKey="Janeba Z" first="Zlatko" last="Janeba">Zlatko Janeba</name><affiliation wicri:level="3"><nlm:aff id="aff1-2040206618813050">Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic</nlm:aff><country xml:lang="fr">République tchèque</country><wicri:regionArea>Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague</wicri:regionArea><placeName><settlement type="city">Prague</settlement><region type="région" nuts="2">Bohême centrale</region></placeName></affiliation></author></analytic><series><title level="j">Antiviral Chemistry & Chemotherapy</title><idno type="ISSN">0956-3202</idno><idno type="eISSN">2040-2066</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>While noncanonic xanthine nucleotides XMP/dXMP play an important role in balancing and maintaining intracellular purine nucleotide pool as well as in potential mutagenesis, surprisingly, acyclic nucleoside phosphonates bearing a xanthine nucleobase have not been studied so far for their antiviral properties. Herein, we report the synthesis of a series of xanthine-based acyclic nucleoside phosphonates and evaluation of their activity against a wide range of DNA and RNA viruses. Two acyclic nucleoside phosphonates within the series, namely 9-[2-(phosphonomethoxy)ethyl]xanthine (PMEX) and 9-[3-hydroxy-2-(phosphonomethoxy)propyl]xanthine (HPMPX), were shown to possess activity against several human herpesviruses. The most potent compound was PMEX, a xanthine analogue of adefovir (PMEA). PMEX exhibited a single digit µM activity against VZV (EC<sub>50</sub> = 2.6 µM, TK<sup>+</sup> Oka strain) and HCMV (EC<sub>50</sub> = 8.5 µM, Davis strain), while its hexadecyloxypropyl monoester derivative was active against HSV-1 and HSV-2 (EC<sub>50</sub> values between 1.8 and 4.0 µM). In contrast to acyclovir, PMEX remained active against the TK<sup>–</sup> VZV 07–1 strain with EC<sub>50</sub> = 4.58 µM. PMEX was suggested to act as an inhibitor of viral DNA polymerase and represents the first reported xanthine-based acyclic nucleoside phosphonate with potent antiviral properties.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bennett, Bd" uniqKey="Bennett B">BD Bennett</name></author><author><name sortKey="Kimball, Eh" uniqKey="Kimball E">EH Kimball</name></author><author><name sortKey="Gao, M" uniqKey="Gao M">M Gao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wheeler, Lj" uniqKey="Wheeler L">LJ Wheeler</name></author><author><name sortKey="Rajagopal, I" uniqKey="Rajagopal I">I Rajagopal</name></author><author><name sortKey="Mathews, Ck" uniqKey="Mathews C">CK. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Antivir Chem Chemother</journal-id><journal-id journal-id-type="iso-abbrev">Antivir. Chem. Chemother</journal-id><journal-id journal-id-type="publisher-id">AVC</journal-id><journal-id journal-id-type="hwp">spavc</journal-id><journal-title-group><journal-title>Antiviral Chemistry & Chemotherapy</journal-title></journal-title-group><issn pub-type="ppub">0956-3202</issn><issn pub-type="epub">2040-2066</issn><publisher><publisher-name>SAGE Publications</publisher-name><publisher-loc>Sage UK: London, England</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30497281</article-id><article-id pub-id-type="pmc">6287304</article-id><article-id pub-id-type="doi">10.1177/2040206618813050</article-id><article-id pub-id-type="publisher-id">10.1177_2040206618813050</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject></subj-group></article-categories><title-group><article-title>Xanthine-based acyclic nucleoside phosphonates with potent antiviral activity against varicella-zoster virus and human cytomegalovirus</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Baszczyňski</surname><given-names>Ondřej</given-names></name><xref ref-type="aff" rid="aff1-2040206618813050">1</xref></contrib><contrib contrib-type="author"><name><surname>Kaiser</surname><given-names>Martin Maxmilian</given-names></name><xref ref-type="aff" rid="aff1-2040206618813050">1</xref></contrib><contrib contrib-type="author"><name><surname>Česnek</surname><given-names>Michal</given-names></name><xref ref-type="aff" rid="aff1-2040206618813050">1</xref></contrib><contrib contrib-type="author"><name><surname>Břehová</surname><given-names>Petra</given-names></name><xref ref-type="aff" rid="aff1-2040206618813050">1</xref></contrib><contrib contrib-type="author"><name><surname>Jansa</surname><given-names>Petr</given-names></name><xref ref-type="aff" rid="aff1-2040206618813050">1</xref></contrib><contrib contrib-type="author"><name><surname>Procházková</surname><given-names>Eliška</given-names></name><xref ref-type="aff" rid="aff1-2040206618813050">1</xref></contrib><contrib contrib-type="author"><name><surname>Dračínský</surname><given-names>Martin</given-names></name><xref ref-type="aff" rid="aff1-2040206618813050">1</xref></contrib><contrib contrib-type="author"><name><surname>Snoeck</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="aff2-2040206618813050">2</xref></contrib><contrib contrib-type="author"><name><surname>Andrei</surname><given-names>Graciela</given-names></name><xref ref-type="aff" rid="aff2-2040206618813050">2</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0003-4654-679X</contrib-id><name><surname>Janeba</surname><given-names>Zlatko</given-names></name><xref ref-type="aff" rid="aff1-2040206618813050">1</xref><xref ref-type="corresp" rid="corresp1-2040206618813050"></xref></contrib><aff id="aff1-2040206618813050"><label>1</label>Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic</aff><aff id="aff2-2040206618813050"><label>2</label>Laboratory of Virology and Chemotheraphy, Rega Institute, Leuven, Belgium</aff></contrib-group><author-notes><corresp id="corresp1-2040206618813050">Zlatko Janeba, Institute of Organic Chemistry and Biochemistry CAS, Flemingovo náměstí 542/2, Prague 16610, Czech Republic. Email: <email>janeba@uochb.cas.cz</email></corresp></author-notes><pub-date pub-type="epub"><day>29</day><month>11</month><year>2018</year></pub-date><pub-date pub-type="collection"><year>2018</year></pub-date><volume>26</volume><elocation-id>2040206618813050</elocation-id><history><date date-type="received"><day>7</day><month>8</month><year>2018</year></date><date date-type="accepted"><day>15</day><month>10</month><year>2018</year></date></history><permissions><copyright-statement>© The Author(s) 2018</copyright-statement><copyright-year>2018</copyright-year><copyright-holder content-type="sage">SAGE Publications</copyright-holder><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/"><license-p>Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (<ext-link ext-link-type="uri" xlink:href="http://www.creativecommons.org/licenses/by-nc/4.0/">http://www.creativecommons.org/licenses/by-nc/4.0/</ext-link>) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (<ext-link ext-link-type="uri" xlink:href="https://us.sagepub.com/en-us/nam/open-access-at-sage">https://us.sagepub.com/en-us/nam/open-access-at-sage</ext-link>).</license-p></license></permissions><abstract abstract-type="short"><p>While noncanonic xanthine nucleotides XMP/dXMP play an important role in balancing and maintaining intracellular purine nucleotide pool as well as in potential mutagenesis, surprisingly, acyclic nucleoside phosphonates bearing a xanthine nucleobase have not been studied so far for their antiviral properties. Herein, we report the synthesis of a series of xanthine-based acyclic nucleoside phosphonates and evaluation of their activity against a wide range of DNA and RNA viruses. Two acyclic nucleoside phosphonates within the series, namely 9-[2-(phosphonomethoxy)ethyl]xanthine (PMEX) and 9-[3-hydroxy-2-(phosphonomethoxy)propyl]xanthine (HPMPX), were shown to possess activity against several human herpesviruses. The most potent compound was PMEX, a xanthine analogue of adefovir (PMEA). PMEX exhibited a single digit µM activity against VZV (EC<sub>50</sub> = 2.6 µM, TK<sup>+</sup> Oka strain) and HCMV (EC<sub>50</sub> = 8.5 µM, Davis strain), while its hexadecyloxypropyl monoester derivative was active against HSV-1 and HSV-2 (EC<sub>50</sub> values between 1.8 and 4.0 µM). In contrast to acyclovir, PMEX remained active against the TK<sup>–</sup> VZV 07–1 strain with EC<sub>50</sub> = 4.58 µM. PMEX was suggested to act as an inhibitor of viral DNA polymerase and represents the first reported xanthine-based acyclic nucleoside phosphonate with potent antiviral properties.</p></abstract><kwd-group><kwd>Acyclic nucleoside phosphonates</kwd><kwd>xanthine</kwd><kwd>PMEX</kwd><kwd>antiviral</kwd><kwd>HCMV</kwd><kwd>VZV</kwd></kwd-group><funding-group><award-group id="award1-2040206618813050"><funding-source id="funding1-2040206618813050"><institution-wrap><institution>Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences</institution><institution-id institution-id-type="FundRef"></institution-id></institution-wrap></funding-source><award-id rid="funding1-2040206618813050">RVO61388963</award-id></award-group></funding-group><custom-meta-group><custom-meta><meta-name>cover-date</meta-name><meta-value>January-December 2018</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>Belgique</li><li>République tchèque</li></country><region><li>Bohême centrale</li></region><settlement><li>Prague</li></settlement></list><tree><country name="République tchèque"><region name="Bohême centrale"><name sortKey="Baszczy Ski, Ond Ej" sort="Baszczy Ski, Ond Ej" uniqKey="Baszczy Ski O" first="Ond Ej" last="Baszczy Ski">Ond Ej Baszczy Ski</name></region><name sortKey=" Esnek, Michal" sort=" Esnek, Michal" uniqKey=" Esnek M" first="Michal" last=" Esnek">Michal Esnek</name><name sortKey="B Ehova, Petra" sort="B Ehova, Petra" uniqKey="B Ehova P" first="Petra" last="B Ehová">Petra B Ehová</name><name sortKey="Dra Nsk, Martin" sort="Dra Nsk, Martin" uniqKey="Dra Nsk M" first="Martin" last="Dra Nsk">Martin Dra Nsk</name><name sortKey="Janeba, Zlatko" sort="Janeba, Zlatko" uniqKey="Janeba Z" first="Zlatko" last="Janeba">Zlatko Janeba</name><name sortKey="Jansa, Petr" sort="Jansa, Petr" uniqKey="Jansa P" first="Petr" last="Jansa">Petr Jansa</name><name sortKey="Kaiser, Martin Maxmilian" sort="Kaiser, Martin Maxmilian" uniqKey="Kaiser M" first="Martin Maxmilian" last="Kaiser">Martin Maxmilian Kaiser</name><name sortKey="Prochazkova, Eliska" sort="Prochazkova, Eliska" uniqKey="Prochazkova E" first="Eliška" last="Procházková">Eliška Procházková</name></country><country name="Belgique"><noRegion><name sortKey="Snoeck, Robert" sort="Snoeck, Robert" uniqKey="Snoeck R" first="Robert" last="Snoeck">Robert Snoeck</name></noRegion><name sortKey="Andrei, Graciela" sort="Andrei, Graciela" uniqKey="Andrei G" first="Graciela" last="Andrei">Graciela Andrei</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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