Tailoring acyclovir prodrugs with enhanced antiviral activity: rational design, synthesis, human plasma stability and in vitro evaluation
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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.
KeywordsAcyclovir Prodrugs Plasma stability HSV-1 HSV-2 Epstein–Barr virus
Herpes simplex virus type 1
Herpes simplex virus type 2
Liquid chromatography–tandem mass spectrometry
Multiple reaction monitoring
Maximum tolerable concentration
Minimum inhibitory concentration
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.
This article does not contain any studies with human participants or animals performed by any of the authors.
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.
- Antman MD, Gudmundsson OS (2007) Case study: valacyclovir: a prodrug of acyclovir. In: Stella VJ, Borchardt RT, Hageman MJ, Oliyai R, Maag H, Tilley JW (eds) Prodrugs: challenges and rewards part 1. Springer, New York, pp 1369–1376. https://doi.org/10.1007/978-0-387-49785-3_54 CrossRefGoogle Scholar
- Bruni G, Maietta M, Maggi L, Mustarelli P, Ferrara C, Berbenni V, Milanese C, Girella A, Marini A (2013) Preparation and physicochemical characterization of acyclovir cocrystals with improved dissolution properties. J Pharm Sci 102(11):4079–4086. https://doi.org/10.1002/jps.23721 CrossRefPubMedGoogle Scholar
- Carey MC, Cahalane MJ (1988) In: Arias IM, Jakoby WB, Popper H, Schachter D, Shafritz DS (eds) In the liver: biology and pathobiology. Raven Press, New York, pp 573–616Google Scholar
- Hofmann A (1988) In: Arias IM, Jakoby WB, Popper H, Schachter D, Shafritz DA (eds) The liver: biology and pathobiology. Raven Press, New York, pp 553–572Google Scholar
- Johnston C, Saracino M, Kuntz S, Magaret A, Selke S, Huang ML, Schiffer JT, Koelle DM, Corey L, Wald A (2012) Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomised, open-label, cross-over trials. Lancet 379(9816):641–647. https://doi.org/10.1016/S0140-6736(11)61750-9 CrossRefPubMedPubMedCentralGoogle Scholar
- Katragadda S, Jain R, Kwatra D, Hariharan S, Mitra AK (2008) Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: interaction with the transporters on Caco-2 cells. Int J Pharm 362(1–2):93–101. https://doi.org/10.1016/j.ijpharm.2008.06.018 CrossRefPubMedPubMedCentralGoogle Scholar
- Kimberlin DW, Whitley RJ (2007) Antiviral therapy of HSV-1 and -2. In: Arvin A, Campadelli-Fiume G, Mocarski E et al (eds) Human herpesviruses: biology, therapy, and immunoprophylaxis. Cambridge University Press, CambridgeGoogle Scholar
- Longerich T, Eisenbach C, Penzel R, Kremer T, Flechtenmacher C, Helmke B, Encke J, Kraus T, Schirmacher P (2005) Recurrent herpes simplex virus hepatitis after liver retransplantation despite acyclovir therapy. Liver Transpl 11(10):1289–1294. https://doi.org/10.1002/lt.20567 CrossRefPubMedGoogle Scholar
- Mukhopadhyay S, Maitra U (2004) Chemistry and biology of bile acids. Curr Sci 87(12):1666–1683Google Scholar
- Pyles RB (2001) The association of herpes simplex virus and Alzheimer’s disease: a potential synthesis of genetic and environmental factors. Herpes J IHMF 8(3):64–68Google Scholar
- Santos CR, Capela R, Pereira CSGP, Valente E, Gouveia L, Pannecouque C, De Clercq E, Moreira R, Gomes P (2009) Structure–activity relationships for dipeptide prodrugs of acyclovir: implications for prodrug design. Eur J Med Chem 44(6):2339–2346. https://doi.org/10.1016/j.ejmech.2008.08.009 CrossRefPubMedGoogle Scholar
- Turley DS, Dietschy JM (1988) In: Arias IM, Jakoby WB, Popper H, Schachter D, Shafritz DS (eds) In the liver: biology and pathobiology. Raven Press, New York, pp 617–641Google Scholar