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Amino Acids

, Volume 50, Issue 8, pp 1131–1143 | Cite as

Tailoring acyclovir prodrugs with enhanced antiviral activity: rational design, synthesis, human plasma stability and in vitro evaluation

  • Radoslav L. Chayrov
  • Evgenios K. Stylos
  • Maria V. Chatziathanasiadou
  • Kiril N. Chuchkov
  • Aleksandra I. Tencheva
  • Androniki D. Kostagianni
  • Tsenka S. Milkova
  • Assia L. Angelova
  • Angel S. Galabov
  • Stoyan A. Shishkov
  • Daniel G. Todorov
  • Andreas G. Tzakos
  • Ivanka G. Stankova
Original Article
  • 63 Downloads

Abstract

Bile acid prodrugs have served as a viable strategy for refining the pharmaceutical profile of parent drugs through utilizing bile acid transporters. A series of three ester prodrugs of the antiherpetic drug acyclovir (ACV) with the bile acids cholic, chenodeoxycholic and deoxycholic were synthesized and evaluated along with valacyclovir for their in vitro antiviral activity against herpes simplex viruses type 1 and type 2 (HSV-1, HSV-2). The in vitro antiviral activity of the three bile acid prodrugs was also evaluated against Epstein–Barr virus (EBV). Plasma stability assays, utilizing ultra-high performance liquid chromatography coupled with tandem mass spectrometry, in vitro cytotoxicity and inhibitory experiments were conducted in order to establish the biological profile of ACV prodrugs. The antiviral assays demonstrated that ACV-cholate had slightly better antiviral activity than ACV against HSV-1, while it presented an eight-fold higher activity with respect to ACV against HSV-2. ACV-chenodeoxycholate presented a six-fold higher antiviral activity against HSV-2 with respect to ACV. Concerning EBV, the highest antiviral effect was demonstrated by ACV-chenodeoxycholate. Human plasma stability assays revealed that ACV-deoxycholate was more stable than the other two prodrugs. These results suggest that decorating the core structure of ACV with bile acids could deliver prodrugs with amplified antiviral activity.

Keywords

Acyclovir Prodrugs Plasma stability HSV-1 HSV-2 Epstein–Barr virus 

Abbreviations

ACV

Acyclovir

HSV-1

Herpes simplex virus type 1

HSV-2

Herpes simplex virus type 2

EBV

Epstein–Barr virus

LC–MS/MS

Liquid chromatography–tandem mass spectrometry

RT

Retention time

ΜRΜ

Multiple reaction monitoring

MTC

Maximum tolerable concentration

MIC

Minimum inhibitory concentration

Notes

Acknowledgements

We thank Dr. Regina Feederle from the German Cancer Research Center, Heidelberg for assistance with immunofluorescence staining, and Dr. Yavor Mitrev from Laboratory “Bulgarian NMR Centre” Institute of Organic Chemistry with Centre of Phytochemistry, Sofia for helpful discussions.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

All authors listed have contributed to conception, design, gathering, analysis, or interpretation of data, and have contributed to the writing and intellectual content of the article. All authors gave informed consent to the submission of this manuscript.

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Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  • Radoslav L. Chayrov
    • 1
  • Evgenios K. Stylos
    • 5
    • 6
  • Maria V. Chatziathanasiadou
    • 5
  • Kiril N. Chuchkov
    • 1
  • Aleksandra I. Tencheva
    • 1
  • Androniki D. Kostagianni
    • 5
  • Tsenka S. Milkova
    • 1
  • Assia L. Angelova
    • 2
    • 3
  • Angel S. Galabov
    • 3
  • Stoyan A. Shishkov
    • 4
  • Daniel G. Todorov
    • 4
  • Andreas G. Tzakos
    • 5
  • Ivanka G. Stankova
    • 1
  1. 1.Department of ChemistrySouth-West University “Neofit Rilski”BlagoevgradBulgaria
  2. 2.Department of Tumor VirologyGerman Cancer Research CenterHeidelbergGermany
  3. 3.Department of Virology, Institute of MicrobiologyBulgarian Academy of SciencesSofiaBulgaria
  4. 4.Laboratory of VirologySofia University “St. Kliment Ohridski”SofiaBulgaria
  5. 5.Section of Organic Chemistry and Biochemistry, Department of ChemistryUniversity of IoanninaIoanninaGreece
  6. 6.Biotechnology Laboratory, Department of Biological Applications and TechnologyUniversity of IoanninaIoanninaGreece

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