From the Guidelines
Zidovudine (AZT) works by inhibiting HIV replication through interference with HIV RNA-dependent DNA polymerase, also known as reverse transcriptase, which is essential for the conversion of viral RNA into DNA 1.
Mechanism of Action
- Zidovudine is a nucleoside analog that, when phosphorylated to its triphosphate form, competes with natural nucleosides for incorporation into the viral DNA strand, thereby terminating DNA synthesis.
- The ZDV triphosphate can also inhibit human cellular DNA polymerases, but this occurs at concentrations much higher than those required to inhibit HIV polymerase 1.
- Additionally, gamma DNA polymerase, which is necessary for mitochondrial replication, may be inhibited by ZDV at concentrations closer to those achievable in vivo 1.
Resistance Mechanisms
- The emergence of resistance to zidovudine can occur through mutations in the HIV reverse transcriptase gene, such as the N348I mutation, which can confer dual resistance to zidovudine and nevirapine by decreasing the ability of nevirapine to inhibit HIV-1 reverse transcriptase and by reducing RNA/DNA template degradation 1.
Clinical Implications
- The use of zidovudine in HIV-infected pregnant women has been shown to reduce the risk of perinatal transmission of HIV by approximately two-thirds when administered antenatally, intrapartum, and postnatally to the infant 1.
From the FDA Drug Label
Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5'-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into the DNA of cells in culture.
The mechanism of action of Zidovudine (azidothymidine, AZT) in relation to DNA replication, RNA transcription, and RNA replication is as follows:
- DNA replication: Zidovudine triphosphate (ZDV-TP) is incorporated into the DNA, causing DNA chain termination.
- RNA transcription: There is no direct effect of zidovudine on RNA transcription.
- RNA replication: Zidovudine inhibits reverse transcriptase (RT), an enzyme that converts RNA into DNA, thereby preventing the replication of the viral RNA genome. 2
From the Research
Mechanism of Action of Zidovudine
The mechanism of action of Zidovudine (AZT) involves the inhibition of viral reverse transcriptase, which is essential for the replication of HIV [ 3, 4]. The triphosphorylated form of AZT competes with thymidine 5'-triphosphate for binding to the HIV reverse transcriptase and also functions as an alternative substrate [ 4 ]. Incorporation of AZT monophosphate results in chain termination, preventing the formation of new proviral DNA [ 3, 4].
DNA Replication
AZT is incorporated into DNA during replication, resulting in chain termination [ 4 ]. The triphosphorylated form of AZT is the active form of the drug, which competes with thymidine 5'-triphosphate for binding to the HIV reverse transcriptase [ 4 ]. AZT-resistant HIV-1 reverse transcriptase can unblock the AZT-terminated primer by an ATP-dependent mechanism [ 5 ].
RNA Transcription and Replication
AZT acts as a chain terminator during reverse transcription of viral RNA into DNA [ 6, 4]. The mechanism of action of AZT involves the inhibition of viral reverse transcriptase, which is essential for the replication of HIV [ 3, 4]. AZT-resistant HIV-1 reverse transcriptase can unblock the AZT-terminated primer during DNA elongation on DNA and RNA templates [ 5 ].
Key Points
- AZT is a potent inhibitor of HIV reverse transcriptase [ 3, 4]
- The triphosphorylated form of AZT is the active form of the drug [ 4 ]
- AZT acts as a chain terminator during reverse transcription of viral RNA into DNA [ 6, 4]
- AZT-resistant HIV-1 reverse transcriptase can unblock the AZT-terminated primer by an ATP-dependent mechanism [ 5 ]