Ribavirin triphosphate

Although its mechanism of action has not been fully elucidated, it appears to interfere with the synthesis of guanosine triphosphate, to inhibit capping of viral messenger RNA, and to inhibit the viral RNA-dependent RNA polymerase of certain viruses. Ribavirin triphosphate inhibits the... 

Mode of action The mode of action has been studied only for the influenza viruses. Ribavirin is first converted to the 5 -phosphate derivatives, the major product being the compound ribavirin-triphosphate (RTP), which has been postulated to exert its antiviral action by inhibiting viral mRNA synthesis. [Note Rhinoviruses and enteroviruses, which contain preformed mRNA and do not need to synthesize mRNA in the host cell to initiate the infection, are relatively resistant to the action of ribavirin.]... 

Until 2001, it was thought that the mechanism of action of ribavirin involved a decrease in cellular guanosine triphosphate (GTP) pools resulting from inhibition of inosine monophosphate dehydrogenase by ribavirin monophosphate. More recently, the mechanism of action for ribavirin has been expanded to include lethal mutagenesis of the viral genome as a result of ribavirin triphosphate utilization by the error-prone viral RNA-dependent RNA polymerase, and incorporation of ribavirin into viral RNA. 

In 2001 a critical stndy published in Nature Medicine showed in vitro nse of ribavirin triphosphate by a model viral RNA polymerase, polioviras 3D pol. Ribavirin incorporation is mutagenic, because it serves as a template for incorporation of cytidine and uridine with equal efficiency (Figure 2-2). Ribavirin reduces infectious poliovirus production to as little as 0.00001 percent in cell culture. The antiviral activity of ribavirin correlates directly with its mutagenic activity. These data indicate that ribavirin forces the virus into error catastrophe. This study reveals a new concept about nucleoside analogs, that is, mutagenic ribonucleosides may represent an important class of anti-RNA virus agents. 

Ribavirin monophosphate competitively inhibits cellular inosine-5 -phosphate dehydrogenase and interferes with the synthesis of guanosine triphosphate (GTP) and, thus, nucleic acid synthesis in general. Ribavirin triphosphate also competitively inhibits the GTP-dependent 5 -capping of viral messenger RNA and, specifically, influenza virus transcriptase activity. Ribavirin appears to have multiple sites of action, and some of these (e.g., inhibition of GTP synthesis) may potentiate others (e.g., inhibition of GTP-dependent enzymes). 

The volume of distribution for ribavirin is large (-10 Ukg) owing to its cellular uptake. Plasma protein binding is negligible. The plasma t, increases to 200-300 hours at steady state, partly because erythrocytes concentrate ribavirin triphosphate and then release it with a of -40 days. Hepatic metabolism and rerml excretion of ribavirin and its metabolites are the principal routes of elimination. Hepatic metabolism involves deribosylation and hydrolysis to a triazole carboxamide. Ribavirin should be used cautiously in patients with creatinine clearances of <50 mUmin. 

The answer is e. (Katzung, p 842.) Ribavirin most likely interferes with guanosine triphosphate synthesis, resulting in inhibition of capping of viral messenger RNA and viral RN A-dependent RNA polymerase. It is effective in moderating infections with respiratory syncytial virus. 

Ribavirin is a synthetic guanosine analogue that possesses broad antiviral inhibitory activity against many viruses, including influenza A and B, parainfluenza, RS V, HCV, HIV-1, and various herpesviruses, arenaviruses, and paramyxoviruses. Its exact mechanism of action has not been fully elucidated however, it appears to inhibit the synthesis of viral mRNA through an effect on nucleotide pools. Following absorption, host cell enzymes convert ribavirin to its monophosphate, diphosphate, and triphosphate forms. Ribavirin monophosphate... 

The synthetic triazole nucleoside, ribavirin (1-beta-D-ribofuranosyl-l,2,4-triazole-3-carboxamide, tribavirin, virazole), has a broad spectrum of antiviral activity, including DNA as well as RNA viruses (1). Ribavirin closely resembles guanosine and is converted intracellu-larly to mono-, di-, and triphosphate derivatives, which inhibit the virally induced enzymes involved in viral nucleic acid synthesis by different mechanisms that are not fully understood (2). Of the DNA viruses, ribavirin is active against Herpes simplex virus and hepatitis B virus among the RNA viruses, good activity has been observed against hepatitis C virus, orthomyxoviruses. 

The antiviral mechanism of action of ribavirin relates to alteration of cellular nucleotide pools and inhibition of viral messenger RNA synthesis. Intracellular phosphorylation to the mono-, di-, and triphosphate derivatives is mediated by host cell enzymes. In both uninfected and RSV-infected cells, the predominant derivative (>80%) is the triphosphate, which has an intracellular t,/2 of elimination of less than 2 hours. 

Ribavirin, a guanosine analogue, has broad-spectrum antiviral aotivity against both DNA and RNA viruses (52,53). It is phosphorylated by adenosine kinase to the triphosphate, resulting in the inhibition of viral specific RNA polymerase, disrupting messenger RNA and nucleio aoid synthesis. 

Ribavirin [13] is a guanosine analog that is intracellularly phosphorylated by the host cell s enzymes. Despite its mechanism is not yet fully elucidated, it apparently interferes with the synthesis of guanosine triphosphate to inhibit capping of viral mRNA and some viral RNA-dependent polymerases. Its triphosphate derivative inhibits the replication of a wide range of RNA and DNA viruses including influenza A and B, parainfluenza, respiratory syncytial virus (RSV), paramyxovirus, HCV and HIV-1. 

A step in the metabolic pathway responsible for the synthesis of guanosine triphosphate (GTP) converts inosine monophosphate (IMP) into xanthosine monophosphate (XMP). Ribavirin is a competitive inhibitor of the enzyme that catalyzes this step. Thus, ribavirin interferes with the synthesis of GTP and, therefore, with the synthesis of nucleic acids. It is used to treat hepatitis C. 

Respiratory syncytial vims (RSV) is a major cause of mortality in yoimg infants and the elderly. The mechanism of action of ribavirin is not entirely clear although it is probable that it acts as an inhibitor of inosine dehydrogenase which is involved in the introduction of a carbonyl group into the inosine stmcture en route to the synthesis of gua-nosine triphosphate (GTP). GTP is required for viral RNA transcription. Ribavirin may also interfere with the action of the viral RNA polymerase. There is some debate over the effectiveness of ribavirin in treating RSV. It is also used in combination with interferon in the treatment of hepatitis C. RSV is also treated with monoclonal antibody therapy and this is discussed in the Chapter 26. 

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