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Ribavirin Derivatives

By , MD, PhD

Ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a purine analogue and a commonly used antiviral agent against both RNA and DNA viruses. With up to five suggested mechanisms of action, latest advances have begun to differentiate the hierarchy of antiviral effects at play depending on the virus and the host conditions under scrutiny.

To minimize ribavirin-induced hemolysis and increase its antiviral effect, considerable efforts have been made involving chemical prodrugs and various formulations. Structure modification of ribavirin and the production of derivatives represent promising approaches in the search for new antiviral agents.

Active derivatives

Ribavirin was initially synthesized using the acid-catalyzed fusion procedure by heating a mixture of the 1-2-4 triazole with catalytic bis(p-nitrophenyl)phosphate and peracetylated sugar at 165 ºC. Derivatives of ribavirin are also prepared by enzymatic synthesis and Vorbrüggen coupling methods.

1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine (TCNR) and 5-amino-TCNR act as competitive reversible inhibitors of human lymphoblast purine nucleoside phosphorylase (PNP). Due to the interaction of the protonated carboxamidine with the glutamine 201 and asparagine 243 residues in PNP active site, the abovementioned derivatives are better substrates for human PNP when compared to ribavirin.

The pyrazole-3-carboxamide derivatives (which are formally considered as 4-deaza-analogues of ribavirin) have shown activity against T-cell lymphocytes and influenza viruses in vitro. Conversely, the 2’ deoxyribose version of ribavirin does not exhibit antiviral activity, suggesting that ribavirin requires RNA-dependent enzymes.

Cytotoxicity of phosphorylated derivatives of ribavirin against lung cancer cell lines (NCI-69) is high. They are synthesized in two principal steps; 4-chlorophenyl dichlorophosphate is initially reacted with various alcohols and amines in the presence of triethylamine, and then further treated with ribavirin using Et3N as a base.

A convenient and simple way to synthesize polymerizable ribavirin derivatives is via transesterification between ribavirin and divinyl dicarboxylates in acetone at 50 ºC, catalyzed by lipase immobilized on acrylic resin from Candida antarctica (CAL-B). These ribavirin esters can be consequently homo-polymerized or copolymerized with other bioactivity compounds such as sugar vinyl esters to form prodrugs which are useful in pharmacy.

Viramidine or taribavirin

One of the most successful ribavirin derivatives to date is viramidine (also known as taribavirin), which was developed by Ripaharm. It is a 3-carboxamidine prodrug of ribavirin, developed to target the liver and subsequently avoid the erythrocyte accumulation (with resulting anemia) often associated with ribavirin therapy.

Pharmacologic studies in rats have revealed that viramidine targets the liver more effectively than ribavirin, as adenosine deaminase conversion of viramidine to ribavirin occurs in the liver, trapping the drug within that organ. Hence this drug may increase adherence to therapy for chronic hepatitis C by reducing the need for dose reduction due to anemia.

Viramidine is available for oral administration and is currently in phase III clinical trials for the treatment of hepatitis C virus infection in combination with pegylated interferon. Although it was primarily developed for this indication, it has also shown broad-spectrum antiviral activity, as well as certain immunomodulatory effects which enhance its antiviral cytotoxic activity even further.

Sources

  1. http://www.liai.org/files/Ribavirin-Crotty.pdf
  2. http://jpck.zju.edu.cn/zhhxsy/cgzs_xscg_xslw056.PDF
  3. www.intmedpress.com/serveFile.cfm
  4. www.researchgate.net/.../02faf4f48024741de7000000.pdf
  5. Simons C. Nucleoside Mimetics: Their Chemistry and Biological Properties. CRC Press, 2000; pp. 83-102.
  6. Wade A, Sasadeusz J. Ribavirin and Viramidine. In: Grayson ML, Crowe SM, McCarthy JS, Mills J, Mouton JW, Norrby SR, Paterson DL, Pfaller MA. Kucers' The Use of Antibiotics Sixth Edition: A Clinical Review of Antibacterial, Antifungal and Antiviral Drugs. CRC Press, 2010; pp. 2923-2958.

Further Reading

Last Updated: Jun 15, 2015

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