Nucleotide Reverse Transcriptase Inhibitors: A Thorough Review, Present Status and Future Perspective as HIV Therapeutics

Abstract

Background: Human immunodeficiency virus type-1 (HIV-1) infection leads to acquired immunodeficiency syndrome (AIDS), a severe viral infection that has claimed approximately 658,507 lives in the US between the years 2010-2014. Antiretroviral (ARV) therapy has proven to inhibit HIV-1, but unlike other viral illness, not cure the infection.

Objective: Among various Food and Drug Administration (FDA)-approved ARVs, nucleoside/ nucleotide reverse transcriptase inhibitors (NRTIs) are most effective in limiting HIV-1 infection. This review focuses on NRTIs mechanism of action and metabolism.

Methods: A search of PubMed (1982-2016) was performed to capture relevant articles regarding NRTI pharmacology.

Results: The current classical NRTIs pharmacology for HIV-1 prevention and treatment are presented. Finally, various novel strategies are proposed to improve the efficacy of NRTIs, which will increase therapeutic efficiency of present-day HIV-1 prevention/treatment regimen.

Conclusion: Use of NRTIs will continue to be critical for successful treatment and prevention of HIV-1.

Keywords: AIDS; Antiretroviral drugs; HIV-1; NRTIs; antiretroviral therapy; nanomedicine.

Fig. (1).

(A) HIV-1 infection pathway and (B) Antiretroviral drug (ARV) action site. The numbers in part (A), describes the ARVs target action site of part (B). vRNA, viral RNA genome; vDNA, complimentary viral DNA.

Fig. (2).

NRTI metabolic pathways. The box represents the NRTIs and its metabolites. The activate metabolites of respective NRTI drugs are presented in the irregular star-shaped structure. In red, respective NRTI drug’s (ddNTPs), natural nucleotide analogues (dNTPs) are been presented. In case of Tenofovir (TFV), Abacavir (ABC) and Didanosine (ddI), the broken arrows and boxes below, represents respective catabolic pathway. NRTI, Nucleotide Reverse Transcriptase Inhibitors; ddNTPs, 2’, 3’-dideoxynucleoside 5’-triphosphates; ddNDPs, 2’, 3’-dideoxynucleoside 5’-diphosphate; ddR-1-P, 2′,3′-dideoxyribose-1-phosphate, ABC, Abacavir; CBV, Carbovir monophosphate, ddI, Didanosine; ddIno, dideoxyinosine; FTC, Emtricitabine; 3TC, Lamivudine; POC, isopropyloxymethyl carbonate; d4T, Stavudine; TFV, Tenofovir; TAF, Tenofovir alafenamide; TDF, Tenofovir disoproxil fumarate; AZT, Zidovudine; MP, Monophosphate; DP, Diphosphate; TP, Triphosphate.