title: Human uridine-cytidine kinase phosphorylation of ribavirin: a convenient method for activation of ribavirin for conjugation to proteins.
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.
authors: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Charity Sisters University Hospital, Vinogradska cesta 29, 10 000, Zagreb, Croatia, lucija.virovic@zg.t-com.hr
authors: Lucija
authors: L
authors: Virovic Jukic
authors: Marko
authors: M
authors: Duvnjak
authors: Catherine H
authors: CH
authors: Wu
authors: George Y
authors: GY
authors: Wu
mesh_terms: D000743:Anemia, Hemolytic / Q000139:chemically induced / Q000201:enzymology; D001212:Asialoglycoproteins / Q000737:chemistry* / Q000627:therapeutic use; D016503:Drug Delivery Systems; D016174:Hepacivirus; D006526:Hepatitis C / Q000150:complications / Q000201:enzymology*; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000821:virology; D009703:Nucleoside-Phosphate Kinase / Q000737:chemistry* / Q000378:metabolism; D009961:Orosomucoid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D010766:Phosphorylation; D012254:Ribavirin / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D001212:Asialoglycoproteins; D009961:Orosomucoid; C017030:asialoorosomucoid; D012254:Ribavirin; C019979:cytidylate kinase; D009703:Nucleoside-Phosphate Kinase