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Antiviral Nucleotides

Antiviral nucleotides are nucleotide analogs that repress the viral reproduction by interfering with several key mechanisms of viral nucleic acid replication. They compete with natural dNTP/NTP substrates for the incorporation into the nascent viral nucleic acid thereby leading to chain termination or mutagenesis (Tab. 2).

In vivo or cell culture experiments can be performed using the non-phosphorylated nucleoside variant of an antiviral nucleotide that is intracellularly metabolized by multiple viral and/or host kinases to its active, the antiviral effect exerting (tri)phosphorylated forms (NMP → NDP → NTP)[7,8].

Alternatively, a number of mono- and triphosphorylated forms of antiviral nucleotides are available for functional in vitro experiments (Tab. 1).

Please refer to the corresponding data sheet for detailed application data.

Table 1: Available antiviral nucleoside and nucleotide analogs.

NucleosideNucleotide
Monophosphate (NMP)
Nucleotide
Triphosphate (NTP)
3TC
(Lamivudine)
3TCMP3TCTP
d4T
(Stavudine)
d4TMPd4TTP
AzT
(Zidovudine)
AzTMPAzTTP
ara-A
(Vidarabine)
ara-AMPara-ATP
AciclovirAciclovir monophosphateAciclovir triphosphate
RibavirinRibavirin monophosphateRibavirin triphosphate
TelbivudineTelbivudine monophosphateTelbivudine triphosphate
6-Aza-U6-Aza-UMP6-Aza-UTP
TenofovirTenofovir diphosphate

Table 2: Antiviral properties of selected nucleotide analogs.

NucleotideAnalog of...Incorporation by viral...Mechanism of inhibition
Lamivudine triphosphate...Cytidine triphosphate...Reverse Transcriptase[1]Chain termination of viral cDNA synthesis
Stavudine triphosphate...Thymidine triphosphate...Reverse Transcriptase[2]Chain termination of viral cDNA synthesis
Zidoduvine triphosphate...Thymidine triphosphate...Reverse Transcriptase[3]Chain termination of viral cDNA synthesis
Aciclovir triphosphate...Guanosine triphosphate...DNA polymerase[4]Chain termination of viral DNA synthesis[4]
Vidarabine triphosphate...Adenosine triphosphate...DNA polymerase[5]unknown
Ribavirin triphosphate...Guanosine triphosphate...RNA polymerase[6]Mutagenesis of viral genome replication[6]

Selected References

1] Huang at al. (2011) Effect of reverse transcriptase inhibitors on Line-1 and Ty1 reverse transcriptase activities and on LINE-1 retrotransposition. BMC Biochemistry 12:18.
[2] Vaccaro at al. (1999) Mechanism of Inhibition of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase by d4TTP: an Equivalent Incorporation Efficiency Relative to the Natural Substrate dTTP. Antimicrob. Agents Chemother. 44 (1):217.
[3] Jaju at al. (1995) Human immunodeficiency virus type 1 reverse transcriptase. 3'-Azidodeoxythymidine 5'-triphosphate inhibition indicates two-step binding for template-primer. J. Biol. Chem. 270 (17):9740.
[4] Furmann at al. (1979) Inhibition of Herpes Simplex Virus-Induced DNA Polymerase Activity and Viral DNA Replication by 9-(2-Hydroxyethoxymethyl)guanine and Its Triphosphate. J. Virol. 29 (2):154.
[5] Muller at al. (1977) Inhibition of Herpesvirus DNA synthesis by 9-O-D-Arabinofuranosyladenine in cellular and cell-free systems. Ann. N.Y. Acad. Sci. 284:34.
[6] Crotty at al. (2000) The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nature Medicine 6 (12):1375.
[7] Ray at al. (2009) Metabolism of antiviral nucleosides and nucleotides. In: Antiviral Research: Strategies in antiviral drug discovery (LaFemina). ASM Press.
[8] Simons at al. (2005) Recent Advances in Antiviral Nucleoside and Nucleotide Therapeutics. Current Topics in Medicinal Chemistry 5:1191.