Effect of the complexation with cyclodextrins on the in vitro antiviral activity of ganciclovir against human cytomegalovirus.
The toxicity of the molecules currently used in the treatment of human cytomegalovirus (HCMV) in immunocompromised hosts often causes interruption of the therapy. Cyclodextrins (Cds), oligosaccharides possessing a hydrophobic cavity, have the property of forming inclusion complexes with a great number of molecules, improving their bioavailability and their biological properties. In this study, we have tested the ability of three native Cds to improve the antiviral effect of ganciclovir (GCV) on two HCMV strains: AD169, a reference susceptible strain, and RC11, a GCV resistant strain. The efficacy of the GCV, expressed in IC50 values, showed no improvement in the presence of alpha-Cd, while the use of beta- and gamma-Cd improved by 6- and 4-fold, respectively, its antiviral activity tested on AD169 strain. The influence of beta- or gamma-Cd on GCV efficiency evaluated on RC11 strain showed a decrease of the IC50. Parallel NMR studies were undertaken in order to characterize formation of [GCV:Cd] complexes. The results showed that complexation between alpha- or gamma-Cd and GCV did not occur. In contrast, spectra proved that beta-Cd formed an inclusion complex with GCV. This complex was characterized in UV-Visible spectrophotometry and the influence of the beta-Cd on the GCV penetration in cells was measured. The use of Cds as carriers of antiviral drugs would be a good alternative to traditional treatment, because it may allow the administration of lower doses and so continuous treatment by reducing the toxic effects of drugs.
Unité Mixte de Recherche Université-CNRS 7565, Structure et Réactivité des Systèmes Moléculaires Complexes, UHP, Nancy, France.
C
C
Nicolazzi
S
S
Abdou
J
J
Collomb
A
A
Marsura
C
C
Finance
D000998:Antiviral Agents / Q000378:metabolism / Q000493:pharmacokinetics; D001682:Biological Availability; D002460:Cell Line; D002470:Cell Survival; D003505:Cyclodextrins / Q000378:metabolism / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000187:drug effects*; D004339:Drug Compounding; D004352:Drug Resistance, Microbial; D004355:Drug Stability; D005347:Fibroblasts / Q000382:microbiology; D015774:Ganciclovir / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure
D000998:Antiviral Agents; D003505:Cyclodextrins; D015774:Ganciclovir