Omeprazole Increases the Efficacy of Acyclovir Against Herpes Simplex Virus Type 1 and 2
Identifieur interne : 000528 ( Pmc/Checkpoint ); précédent : 000527; suivant : 000529Omeprazole Increases the Efficacy of Acyclovir Against Herpes Simplex Virus Type 1 and 2
Auteurs : Martin Michaelis [Royaume-Uni] ; Malte C. Kleinschmidt [Allemagne] ; Denisa Bojkova [Allemagne] ; Holger F. Rabenau [Allemagne] ; Mark N. Wass [Royaume-Uni] ; Jindrich Cinatl Jr. [Allemagne]Source :
- Frontiers in Microbiology [ 1664-302X ] ; 2019.
Abstract
Omeprazole was shown to improve the anti-cancer effects of the nucleoside analogue 5-fluorouracil. Here, we combined omeprazole with the antiviral nucleoside analogues ribavirin and acyclovir. Omeprazole did not affect the antiviral effects of ribavirin in non-toxic concentrations up to 80 μg/mL but increased the acyclovir-mediated effects on herpes simplex virus 1 and 2 (HSV-1 and -2) replication in a dose-dependent manner. Omeprazole alone reduced HSV-1 and -2 titers [but not HSV-induced formation of cytopathogenic effects (CPE)] at concentrations ≥40 μg/mL. However, it exerted substantially stronger effects on acyclovir activity and also increased acyclovir activity at lower concentrations that did not directly interfere with HSV replication. Omeprazole 80 μg/mL caused a 10.8-fold (Vero cells) and 47.7-fold (HaCaT cells) decrease of the acyclovir concentrations that reduced HSV-1-induced CPE formation by 50% (IC50). In HSV-2-infected cells, omeprazole 80 μg/mL reduced the acyclovir IC50 by 7.3- (Vero cells) and 12.9-fold (HaCaT cells). In HaCaT cells, omeprazole 80 μg/mL reduced the HSV-1 titer in the presence of acyclovir 1 μg/mL by 1.6 × 105-fold and the HSV-2 titer in the presence of acyclovir 2 μg/mL by 9.2 × 103-fold. The proton pump inhibitors pantoprazole, rabeprazole, lansoprazole, and dexlansoprazole increased the antiviral effects of acyclovir in a similar fashion as omeprazole, indicating this to be a drug class effect. In conclusion, proton pump inhibitors increase the anti-HSV activity of acyclovir and are candidates for antiviral therapies in combination with acyclovir, in particular for topical preparations for the treatment of immunocompromised individuals who are more likely to suffer from severe complications.
Url:
DOI: 10.3389/fmicb.2019.02790
PubMed: 31849920
PubMed Central: 6901432
Affiliations:
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Omeprazole Increases the Efficacy of Acyclovir Against Herpes Simplex Virus Type 1 and 2</title>
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<author><name sortKey="Kleinschmidt, Malte C" sort="Kleinschmidt, Malte C" uniqKey="Kleinschmidt M" first="Malte C." last="Kleinschmidt">Malte C. Kleinschmidt</name>
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<author><name sortKey="Bojkova, Denisa" sort="Bojkova, Denisa" uniqKey="Bojkova D" first="Denisa" last="Bojkova">Denisa Bojkova</name>
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<front><div type="abstract" xml:lang="en"><p>Omeprazole was shown to improve the anti-cancer effects of the nucleoside analogue 5-fluorouracil. Here, we combined omeprazole with the antiviral nucleoside analogues ribavirin and acyclovir. Omeprazole did not affect the antiviral effects of ribavirin in non-toxic concentrations up to 80 μg/mL but increased the acyclovir-mediated effects on herpes simplex virus 1 and 2 (HSV-1 and -2) replication in a dose-dependent manner. Omeprazole alone reduced HSV-1 and -2 titers [but not HSV-induced formation of cytopathogenic effects (CPE)] at concentrations ≥40 μg/mL. However, it exerted substantially stronger effects on acyclovir activity and also increased acyclovir activity at lower concentrations that did not directly interfere with HSV replication. Omeprazole 80 μg/mL caused a 10.8-fold (Vero cells) and 47.7-fold (HaCaT cells) decrease of the acyclovir concentrations that reduced HSV-1-induced CPE formation by 50% (IC<sub>50</sub>
). In HSV-2-infected cells, omeprazole 80 μg/mL reduced the acyclovir IC<sub>50</sub>
by 7.3- (Vero cells) and 12.9-fold (HaCaT cells). In HaCaT cells, omeprazole 80 μg/mL reduced the HSV-1 titer in the presence of acyclovir 1 μg/mL by 1.6 × 10<sup>5</sup>
-fold and the HSV-2 titer in the presence of acyclovir 2 μg/mL by 9.2 × 10<sup>3</sup>
-fold. The proton pump inhibitors pantoprazole, rabeprazole, lansoprazole, and dexlansoprazole increased the antiviral effects of acyclovir in a similar fashion as omeprazole, indicating this to be a drug class effect. In conclusion, proton pump inhibitors increase the anti-HSV activity of acyclovir and are candidates for antiviral therapies in combination with acyclovir, in particular for topical preparations for the treatment of immunocompromised individuals who are more likely to suffer from severe complications.</p>
</div>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Front Microbiol</journal-id>
<journal-id journal-id-type="iso-abbrev">Front Microbiol</journal-id>
<journal-id journal-id-type="publisher-id">Front. Microbiol.</journal-id>
<journal-title-group><journal-title>Frontiers in Microbiology</journal-title>
</journal-title-group>
<issn pub-type="epub">1664-302X</issn>
<publisher><publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31849920</article-id>
<article-id pub-id-type="pmc">6901432</article-id>
<article-id pub-id-type="doi">10.3389/fmicb.2019.02790</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Microbiology</subject>
<subj-group><subject>Original Research</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Omeprazole Increases the Efficacy of Acyclovir Against Herpes Simplex Virus Type 1 and 2</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Michaelis</surname>
<given-names>Martin</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/19228/overview"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Kleinschmidt</surname>
<given-names>Malte C.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/830782/overview"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Bojkova</surname>
<given-names>Denisa</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rabenau</surname>
<given-names>Holger F.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wass</surname>
<given-names>Mark N.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/104376/overview"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Cinatl Jr.</surname>
<given-names>Jindrich</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="corresp" rid="c001"><sup>*</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/536948/overview"></uri>
</contrib>
</contrib-group>
<aff id="aff1"><sup>1</sup>
<institution>Industrial Biotechnology Centre, School of Biosciences, University of Kent</institution>
,<addr-line>Canterbury</addr-line>
,<country>United Kingdom</country>
</aff>
<aff id="aff2"><sup>2</sup>
<institution>Institut für Medizinische Virologie, Klinikum der Goethe-Universität</institution>
,<addr-line>Frankfurt am Main</addr-line>
,<country>Germany</country>
</aff>
<author-notes><fn fn-type="edited-by"><p>Edited by: Michael Nevels, University of St Andrews, United Kingdom</p>
</fn>
<fn fn-type="edited-by"><p>Reviewed by: Junji Xing, Houston Methodist Research Institute, United States; Oliver H. Krämer, Johannes Gutenberg University Mainz, Germany</p>
</fn>
<corresp id="c001">*Correspondence: Jindrich Cinatl Jr., <email>Cinatl@em.uni-frankfurt.de</email>
</corresp>
<fn fn-type="other" id="fn004"><p>This article was submitted to Virology, a section of the journal Frontiers in Microbiology</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>03</day>
<month>12</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><year>2019</year>
</pub-date>
<volume>10</volume>
<elocation-id>2790</elocation-id>
<history><date date-type="received"><day>17</day>
<month>7</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>18</day>
<month>11</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2019 Michaelis, Kleinschmidt, Bojkova, Rabenau, Wass and Cinatl.</copyright-statement>
<copyright-year>2019</copyright-year>
<copyright-holder>Michaelis, Kleinschmidt, Bojkova, Rabenau, Wass and Cinatl</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p>
</license>
</permissions>
<abstract><p>Omeprazole was shown to improve the anti-cancer effects of the nucleoside analogue 5-fluorouracil. Here, we combined omeprazole with the antiviral nucleoside analogues ribavirin and acyclovir. Omeprazole did not affect the antiviral effects of ribavirin in non-toxic concentrations up to 80 μg/mL but increased the acyclovir-mediated effects on herpes simplex virus 1 and 2 (HSV-1 and -2) replication in a dose-dependent manner. Omeprazole alone reduced HSV-1 and -2 titers [but not HSV-induced formation of cytopathogenic effects (CPE)] at concentrations ≥40 μg/mL. However, it exerted substantially stronger effects on acyclovir activity and also increased acyclovir activity at lower concentrations that did not directly interfere with HSV replication. Omeprazole 80 μg/mL caused a 10.8-fold (Vero cells) and 47.7-fold (HaCaT cells) decrease of the acyclovir concentrations that reduced HSV-1-induced CPE formation by 50% (IC<sub>50</sub>
). In HSV-2-infected cells, omeprazole 80 μg/mL reduced the acyclovir IC<sub>50</sub>
by 7.3- (Vero cells) and 12.9-fold (HaCaT cells). In HaCaT cells, omeprazole 80 μg/mL reduced the HSV-1 titer in the presence of acyclovir 1 μg/mL by 1.6 × 10<sup>5</sup>
-fold and the HSV-2 titer in the presence of acyclovir 2 μg/mL by 9.2 × 10<sup>3</sup>
-fold. The proton pump inhibitors pantoprazole, rabeprazole, lansoprazole, and dexlansoprazole increased the antiviral effects of acyclovir in a similar fashion as omeprazole, indicating this to be a drug class effect. In conclusion, proton pump inhibitors increase the anti-HSV activity of acyclovir and are candidates for antiviral therapies in combination with acyclovir, in particular for topical preparations for the treatment of immunocompromised individuals who are more likely to suffer from severe complications.</p>
</abstract>
<kwd-group><kwd>HSV</kwd>
<kwd>HSV-1</kwd>
<kwd>HSV-2</kwd>
<kwd>antiviral therapy</kwd>
<kwd>antiviral drugs</kwd>
<kwd>ribavirin</kwd>
<kwd>proton pump inhibitors</kwd>
</kwd-group>
<counts><fig-count count="4"></fig-count>
<table-count count="0"></table-count>
<equation-count count="0"></equation-count>
<ref-count count="38"></ref-count>
<page-count count="7"></page-count>
<word-count count="0"></word-count>
</counts>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Allemagne</li>
<li>Royaume-Uni</li>
</country>
</list>
<tree><country name="Royaume-Uni"><noRegion><name sortKey="Michaelis, Martin" sort="Michaelis, Martin" uniqKey="Michaelis M" first="Martin" last="Michaelis">Martin Michaelis</name>
</noRegion>
<name sortKey="Wass, Mark N" sort="Wass, Mark N" uniqKey="Wass M" first="Mark N." last="Wass">Mark N. Wass</name>
</country>
<country name="Allemagne"><noRegion><name sortKey="Kleinschmidt, Malte C" sort="Kleinschmidt, Malte C" uniqKey="Kleinschmidt M" first="Malte C." last="Kleinschmidt">Malte C. Kleinschmidt</name>
</noRegion>
<name sortKey="Bojkova, Denisa" sort="Bojkova, Denisa" uniqKey="Bojkova D" first="Denisa" last="Bojkova">Denisa Bojkova</name>
<name sortKey="Cinatl Jr, Jindrich" sort="Cinatl Jr, Jindrich" uniqKey="Cinatl Jr J" first="Jindrich" last="Cinatl Jr.">Jindrich Cinatl Jr.</name>
<name sortKey="Rabenau, Holger F" sort="Rabenau, Holger F" uniqKey="Rabenau H" first="Holger F." last="Rabenau">Holger F. Rabenau</name>
</country>
</tree>
</affiliations>
</record>
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