Human uridine-cytidine kinase phosphorylation of ribavirin: a convenient method for activation of ribavirin for conjugation to proteins |
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Authors: | Lucija Virovic Jukic Marko Duvnjak Catherine H Wu George Y Wu |
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Institution: | (1) Department of Internal Medicine, Division of Gastroenterology and Hepatology, Charity Sisters University Hospital, Vinogradska cesta 29, 10 000 Zagreb, Croatia;(2) Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA |
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Abstract: | Ribavirin is a synthetic nucleoside analog that is used for the treatment of hepatitis C virus (HCV) infection. Its primary
toxicity is hemolytic anemia, which sometimes necessitates dose reduction or discontinuation of therapy. Selective delivery
of ribavirin into liver cells would be desirable to enhance its antiviral activity and avoid systemic side effects. One approach
to liver-specific targeting is conjugation of the ribavirin with asialoglycoprotein that is taken up specifically by liver
cells. Human uridine-cytidine kinase-1 (UCK-1) was used for ribavirin phosphorylation to its monophosphate form. 1-Ethyl-3-diisopropylaminocarbodiimide
(EDC) was used as a coupling agent. The best results were obtained using direct conjugation protocol with a molar ratio of
6.5 ribavirin monophosphate (RMP) molecules per one asialoorosomucoid (AsOR) molecule. Our findings show that ribavirin is
a potential substrate of UCK-1, and RMP formed could be chemically coupled to AsOR to form a conjugate for liver specific
targeting. |
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Keywords: | Ribavirin Phosphorylation Human uridine-cytidine kinase-1 Protein conjugation Carbodiimide |
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