Guanosine analogue

Fig. 7. Adenosine and guanosine analogues with both RNA and DNA antiviral effectiveness.

All acyclic and carbocyclic guanosine analogues depicted in Fig. 1 follow the same modus operandi as exemplified for acyclovir (ACV) in Fig. 5, in that they need three phosphorylations to be converted to their active metabolite, the triphosphate form, which then interacts with the target enzyme, the viral DNA polymerase, as a chain terminator (De Clercq 2002). In its DNA chain-terminating... 

All NRTIs, as exemplified for AZT (Fig. 7), act in a similar fashion following their uptake by the cells, they are phosphorylated successively to their 5 -monophosphate, 5 -diphosphate, and 5 -triphosphate form (De Clercq 2002). Unlike the first phosphorylation step in the metabolic pathway of the acyclic guanosine analogues (see above), which is carried out by a virus-encoded enzyme (thymidine kinase), the first as well as the subsequent phosphorylations of the 2, 3 -dideoxynucleosides are carried out by cellular enzymes, that is, a 2 -deoxynucleoside (e.g., dThd) kinase, a 2 -deoxynucleotide (e.g., dTMP) kinase, and a (2 -deoxy)nucleoside 5 -diphosphate (NDP) kinase. 

Interferon alfa-2a (Roferon A), interferon alfa-2b (Intron-A), and interferon alfacon-1 (Infergen) are approved for chronic hepatitis C. However, they are not prescribed alone because only 12% to 16% of patients achieve a sustained virologic response (SVR). Adding ribavirin, a synthetic guanosine analogue that inhibits viral polymerase, increases the SVR rate to 35% to 45%. 

Famciclovir (Famvir) is the diacetyl ester prodrug of the acyclic guanosine analogue 6-deoxypenciclovir Dena-vir). Penciciovir has activity against HSV-1, HSV-2, VZV, and HB V. After oral administration, famciclovir is converted to penciciovir by first-pass metabolism. Penciciovir has a mechanism of action similar to that of acyclovir. It is first monophosphorylated by viral thymidine kinase then it is converted to a triphosphate by cellular kinases. Penciciovir triphosphate acts as a competitive inhibitor of viral DNA polymerase, but unlike acyclovir, it does not cause chain termination. 

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... 

Ribavirin This guanosine analogue was first used experimentally by o. Reichard et al. (1991) and in chronic hepatitis C by J. Andersson et al. (1991). It is rapidly absorbed and distributed in the body, but is excreted slowly (half-life 79 hours). The bioavailability is 45-65%. As a monotherapy, it only leads to a decrease in transaminases and a slight improvement in histological activity. Ribavirin may not exhibit a direct antiviral effect, but can trigger a favourable response to interferon. When combined with IFN, ribavirin proved far more efficacious in chronic hepatitis C (immunomo-dulation ) without any increase in the typical side effects of IFN. (49, 51, 53) (s. p. 707)... 

Oral guanosine analogue with antiviral activity against variety of RNA and DNA viruses. For HCV infections, combination of ribavirin plus interferon improves virologic response compared to interferon monotherapy. 

Oxanosine, a novel guanosine analogue antibiotic has been phosphorylated according to the Yoshikawa procedure to yield (17) and evaluated for in vitro antiviral activity against HIV proliferation. Compound (17) reduced the number of HIV particles in CEM cells to almost the same level as ddl. 

Ribavirin is a synthetic guanosine analogue, with in vitro activity against a broad spectrum of DNA and RNA viruses, and retroviruses, including HIV. Ribavirin has been used for treatment of a variety of viral infections, including respiratory syncytial virus bronchiolitis and pneumonia, measles, influenza types A and B, Lassa fever, hemorrhagic fever with renal syndrome (Hantaviruses), hepatitis C, and HIV infection. It is used commonly now along with interferon alpha for treatment of hepatitis C infection. There is no known direct nephrotoxicity of ribavirin. 

A fluorescent guanosine analogue has been synthesised and incorporated into oligonucleotides using the synthon (181). The fluorophore within DNA has been used to develop a continuous fluorescence assay for the HFV-l integrase 3 -processing reaction. 

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. 

Two guanosine analogues were designed and synthesized by our group through connecting one (13a) or three adamantane branches (13b, Fig. 3.10) [33]. By means of circular dichroism and UV/visible spectra, NMR, SEM, and stmcmral studies. 

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