nucleoside reverse

transacripts inhibitors

(NRTIs)

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) are a class of antiretroviral drugs critical for treating HIV infection. They work by mimicking natural nucleosides, the building blocks of viral DNA, but lack the 3′-hydroxyl group required to form DNA chain bonds. When incorporated during reverse transcription—the process where HIV converts its RNA into DNA—NRTIs terminate viral DNA synthesis, halting replication.

Mechanism:

            • Chain termination: NRTIs are phosphorylated into active triphosphate forms by host enzymes. These analogs compete with natural nucleotides for incorporation into viral DNA by reverse transcriptase. Once added, they block further elongation due to their missing 3′-hydroxyl group.

            • Competitive inhibition: They target both viral and host DNA synthesis, explaining their antiviral effects and side effects.

Clinical Use:

NRTIs remain foundational in highly active antiretroviral therapy (HAART) despite newer drug classes like NNRTIs and protease inhibitors. Their role in preserving the efficacy of other antiretrovirals and preventing cross-resistance is indispensable.

Examples:

Common NRTIs include zidovudine (AZT), lamivudine (3TC), and emtricitabine (FTC). Newer agents like tenofovir (a nucleotide analog) simplify activation pathways to enhance potency and reduce toxicity.

Challenges:

NRTIs are linked to mitochondrial toxicity (e.g., lactic acidosis, peripheral neuropathy) due to inhibition of human DNA polymerase gamma, which maintains mitochondrial DNA. However, some newer agents like tenofovir show lower affinity for this enzyme, potentially improving safety.

Indications of Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

NRTIs are primarily used to treat HIV and HBV infections by blocking the reverse transcriptase enzyme, preventing viral replication.

Key Indications

            •  HIV Treatment: Core component of antiretroviral therapy (ART), often combined with other drug classes (e.g., integrase inhibitors).

            •  Recommended NRTIs: TAF/FTC, TDF/FTC, and DTG/3TC are preferred for initial ART due to efficacy and safety.

            • Avoided NRTIs: Older agents like zidovudine (ZDV) and stavudine (d4T) due to severe toxicity.

            •  HBV Treatment: Lamivudine (3TC) and tenofovir (TDF/TAF) have anti-HBV activity but require combination therapy to prevent resistance.

            • Off-Label/Experimental: Some studies suggest potential against SARS-CoV-2 by targeting viral RNA-dependent RNA polymerase (RdRp), though clinical evidence remains limited.

Mechanism: NRTIs are phosphorylated into active forms, incorporated into viral DNA during reverse transcription, causing chain termination.

Safety: Newer NRTIs (e.g., TAF) have reduced renal/toxicity risks compared to older agents like TDF. Mitochondrial toxicity remains a concern with prolonged use.