Nucleoside Reverse Transcriptase Inhibitors

Inhibition mechanism

Once HIV has entered the target host cell reverse transcription, initiated by the viral reverse transcriptase (RT) enzyme, occurs. During reverse transcription the HIV RNA genome is reverse transcribed to DNA which will be transported into the nucleus and integrated into the host genome for subsequent replication. Nucleoside reverse transcriptase inhibitors (NRTIs) are structural nucleoside analogues of DNA nucleotides which prevent reverse transcription of the HIV genome, thereby inhibiting the action of HIV-1 RT and viral replication . These nucleosides are defective in the sense that they prevent new 3' phosphodiesterase bonds with the next nucleotide in a growing DNA strand . These nucleoside analogues are phosphorylated by human cellular kinases to their triphosphate form where they are subsequently incorporated by RT into the growing DNA primer strand of HIV. This results in premature chain termination and the inhibition of successful HIV replication .

Side-effects and metabolism

These drugs have been found highly effective for the treatment of HIV-1 and are generally regarded as safe to use but life-threatening adverse reactions, like mitochondrial toxicity, have been reported . Mitochondrial toxicity occurs due to the ability of NRTIs, except abacavir and lamivudine, to compete with human mitochondrial DNA polymerase gamma . This polymerase is responsible for excision repair of mitochondrial DNA that has been damaged by oxidation. Decrease in mitochondrial DNA excision repair results in a depletion of mitochondrial DNA and the subsequent disruption of oxidative phosphorylation leading to toxin accumulation and mitochondrial toxicity .

NRTIs have no CYP 450 interactions . They are subject to interactions of glucuronidation and absorption and metabolism differs with each drug.