An introduction to nucleoside and nucleotide analogues

Area of Science:

• Pharmacology and Virology
• Antiretroviral Therapy
• Mitochondrial Toxicology

Background:

• Nucleoside analogue reverse transcriptase inhibitors (NRTIs) are essential in highly active antiretroviral therapy (HAART) for HIV suppression.
• Current NRTIs face limitations due to class-related adverse events, including mitochondrial toxicity, lactic acidaemia, and hepatic steatosis.
• These toxicities are linked to NRTI affinity for mitochondrial DNA polymerase gamma, impacting long-term safety.

Purpose of the Study:

• To highlight the enduring importance of NRTIs in HAART regimens.
• To address the need for new antiretroviral agents with improved virological potency and long-term safety.
• To introduce nucleotide analogue reverse transcriptase inhibitors (NtRTIs) as a potential solution.

Main Methods:

• Review of existing literature on NRTI mechanisms, efficacy, and toxicity.
• Discussion of the development and preclinical/clinical evaluation of NtRTIs.
• Focus on tenofovir disoproxil fumarate (TDF) as a leading NtRTI candidate.

Main Results:

• NRTIs, despite limitations, are crucial for maintaining HIV suppression and preserving other drug classes.
• Tenofovir disoproxil fumarate (TDF) demonstrates high potency and durable responses in treatment-experienced individuals.
• TDF's active metabolite shows low affinity for mitochondrial DNA polymerase gamma, suggesting reduced mitochondrial toxicity.

Conclusions:

• NRTIs will remain integral to HAART, necessitating strategies to mitigate their adverse effects.
• NtRTIs, exemplified by TDF, represent a promising 'second-generation' nucleoside analogue class.
• NtRTIs are expected to enhance therapeutic options for HIV patients due to improved potency and safety profiles.