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.
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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
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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.
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Chayrov, R.L., Stylos, E.K., Chatziathanasiadou, M.V. et al. Tailoring acyclovir prodrugs with enhanced antiviral activity: rational design, synthesis, human plasma stability and in vitro evaluation. Amino Acids 50, 1131–1143 (2018). https://doi.org/10.1007/s00726-018-2590-y
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DOI: https://doi.org/10.1007/s00726-018-2590-y