Coupling of Antiviral Nucleoside Analogs to Lactosaminated Human Albumin by Using the Imidazolides of Their Phosphoric Esters

Fiume, L.; Busi, C.; Distefano, G.; Mattioli, A.

doi:10.1006/abio.1993.1348

Cited by 21 publications

(12 citation statements)

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“…HRC 203 was prepared as described. 13 Ribavirin (Inter-Chemical, Shenzen, China) in phosphate-buffered saline (PBS) was phosphorylated at its 5Јhydroxyl group according to established methods 19 and subsequently activated to a phosphorimidazolide according to the method of Fiume et al 20 Ribavirin-phosphorimidazolide was reacted in a 150-fold excess with human carbonmonoxyhemoglobin (Hemosol Corp., Mississauga, Ontario, Canada) in 0.1 mol/L sodium bicarbonate buffer, pH 9.5, resulting in phosphoramidate attachment to protein amino groups. The molar drug ratio of the hemoglobin-ribavirin (Hb-RV) conjugate was determined to be 6 to 8 ribavirin molecules per hemoglobin with little or no unmodified hemoglobin remaining after 96 hours of reaction.…”

Section: Methodsmentioning

confidence: 99%

Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity

Levy

Adamson²,

Phillips

et al. 2006

Hepatology

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Side effects of interferon-ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the efficacy of a hemoglobin-ribavirin conjugate ( C hronic hepatitis C virus (HCV) infection is a major public health problem affecting over 4 million people in the United States and more than 170 million individuals worldwide. 1,2 In addition, chronic HCV is a causative factor for approximately 50% of the cases of hepatocellular carcinoma in the United States, and is the single most common indication for orthotopic liver transplantation worldwide. 3,4 However, treatment of HCV infection remains problematic. The current standard of care is a combination of interferon alpha (IFN-␣) and ribavirin. This combination treatment is limited by severe side effects that often lead to premature cessation of therapy. 5 The major toxicity associated with ribavirin is a dose-dependent hemolytic anemia, which occurs in approximately 50% of treated individuals, resulting in a ribavirin dose reduction. 6 The development of anemia usually starts after 4 weeks of therapy and can be precipitous.Coupling of ribavirin to a carrier molecule offers the potential of a therapeutic with improved safety and efficacy by targeting drug delivery of ribavirin to key tissues infected by HCV while preventing the hemolytic anemia that is caused by exposure of red blood cells to free ribavirin. Targeting of drugs by attachment to carrier molecules for delivery to specific tissues via receptor-mediated endocytosis is a recently established method for improv-

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Section: Methodsmentioning

confidence: 99%

Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity

Levy

Adamson²,

Phillips

et al. 2006

Hepatology

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“…Another useful natural function of serum albumin in an organism is to maintain osmotic pressure in the blood vessels; therefore, the solutions of this protein are often used as a plasma substitute in the case of large volume of blood loss. Along with the above advantages of serum albumin, its attractiveness for use as a drug carrier is due to the presence of a large number of side amino, carboxyl, amide and other functional groups in its structure [6,7]. There are known examples of serum albumin application to prolong the action of drugs of protein origin such as "Albuferon" and "Levemir" [8,9].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Comparative Study of Nanoparticles Derived from Bovine and Human Serum Albumins

et al. 2020

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This study describes the preparation of nanoparticles derived from bovine serum albumin (BSA) in comparison with the formation of nanoparticles composed of human serum albumin (HSA), when the same preparation procedure was used in both cases. To obtain protein nanoparticles, the method of desolvation with ethanol was employed, followed by the stabilization with urea and cysteine. It was shown that, upon transition from HSA to BSA, the particles with smaller sizes and with a narrower polydispersity were formed. The possibility of the immobilization of the antitumor drug hydroxyurea in such protein nanoparticles by adsorption and inclusion methods has been shown. The drug release profile from the polymer matrix was established.

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“…Ribavirin was coupled to a high molecular mass lactosaminated poly-L-lysine, a hepatotropic carrier that enabled intramuscular administration of conjugate [41,42]. Conjugation of nucleoside analogs was obtained via the imidazolides of their 5 0 -phosphoric esters [43]. Using this procedure, nucleoside analogs were linked to lysine residues of lactosylated human serum albumin by a phosphate bond.…”

Section: Discussionmentioning

confidence: 99%

“…Ribavirin-5 0 -monophosphate was prepared by reaction of ribavirin with phosphorus oxychloride and trimethyl phosphate according to the method of Allen [45]. Purified RMP was converted to ribavirin-5 0 -phosphorimidazolide according to the procedure of Fiume [43], and was then conjugated to hemoglobin. The molar drug ratio of the product achieved was between 6 and 8 ribavirin moieties attached per hemoglobin tetramer.…”

Section: Discussionmentioning

confidence: 99%

Human uridine-cytidine kinase phosphorylation of ribavirin: a convenient method for activation of ribavirin for conjugation to proteins

Jukić

Duvnjak

et al. 2007

J Biomed Sci

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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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Coupling of Antiviral Nucleoside Analogs to Lactosaminated Human Albumin by Using the Imidazolides of Their Phosphoric Esters

Cited by 21 publications

References 0 publications

Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity

Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity

Synthesis and Comparative Study of Nanoparticles Derived from Bovine and Human Serum Albumins

Human uridine-cytidine kinase phosphorylation of ribavirin: a convenient method for activation of ribavirin for conjugation to proteins

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