Mechanisms of nucleoside analog antiviral activity and resistance during human immunodeficiency virus reverse transcription

Arts, Eric J.; Wainberg, Mark A.

doi:10.1128/aac.40.3.527

Cited by 121 publications

(66 citation statements)

References 182 publications

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“…(3). The initial metabolic activation of these molecules is the phosphorylation of their 5'-triphosphate derivates, which allows them to act as competitive inhibitors or alternative substrates of HIV-1 RT for their eventual incorporation into the viral DNA chain [56]. Once these drugs are incorporated into the growing viral DNA chain, the process is aborted and the DNA elongates no further.…”

Section: Hiv-1 Rt Inhibitorsmentioning

confidence: 99%

HIV-1 Reverse Transcriptase: A Therapeutical Target in the Spotlight

Castro¹,

Loureiro²,

Pujol-Luz³

et al. 2006

CMC

104

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Human Immunodeficiency Virus type 1 Reverse Transcriptase (HIV-1 RT) is one of the most important targets for treatment of Acquired Immune Deficiency Syndrome (AIDS). It catalyzes the reverse transcription of HIV-RNA into a double stranded DNA, and the knowledge of its substrate specificity and catalytic mechanism has guided the development of several inhibitors widely used on current HIV/AIDS therapy. However, mutations in HIV-1 RT structure can lead to the emergence of drug-resistant virus strains. The goal of this review is to summarize relevant structural features of HIV-1 RT and its inhibitors in such a way that this cost-effective target in the development of new antiretroviral drugs is particularly highlighted.

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Section: Hiv-1 Rt Inhibitorsmentioning

confidence: 99%

HIV-1 Reverse Transcriptase: A Therapeutical Target in the Spotlight

Castro¹,

Loureiro²,

Pujol-Luz³

et al. 2006

CMC

104

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“…The design of integrase inhibitors is covered in review published in this issue. The development of the anti-HIV nucleoside and non-nucleoside analogs targeted HIV RT and currently employed in clinical trials or licensed for AIDS therapy one can find in excellent reviews of E. De Clercq [8], J. Balzarini and E. De Clercq [9], E. Art and M. Wainberg [10]. Detailed mechanism of interaction of nucleoside 5'-triphosphate (dNTP) analogs with HIV RT one can find in the review of Furman et al, in this issue.…”

Section: Introductionmentioning

confidence: 99%

Design of Anti-HIV Compounds from Nucleoside to Nucleoside 5-Triphosphate Analogs. Problems and Perspectives

Kukhanova¹,

Krayevsky²,

Prusoff³

et al. 2000

CPD

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To date, human immunodeficiency virus infection remains incurable although a variety of antiviral agents have been identified and characterized. Even though nucleoside analogs have been the most successful prodrugs, there remains the need to develop new compounds that exhibit a more favorable toxicity profile, less susceptible to cross-resistance, and greater efficacy. As prodrugs, the nucleoside analogs should be sequentially phosphorylated by cellular kinases to yield triphosphate form before they can inhibit HIV replication at the reverse transcriptase level. The efficiency of phosphorylation of nucleoside analogs is a key factor in their antiviral activity and strongly depends on nucleoside structure and cell type. In recent years, several attempts have been made to improve therapeutic potential of nucleoside analogs by the use of nucleotide prodrugs (pronucleotides), that can avoid the first step of phosphorylation. This review focuses on problems of intracellular phosphorylation of nucleoside analogs and perspectives of developing of a new class of nucleotide analogs modified at phosphate group as a form for the delivery of nucleotide analogs into the cell.

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“…The inhibition of reverse transcriptase (RT, the key enzyme involved in the conversion of viral RNA to DNA) is crucial for arresting the replication of HIV. One of the first potent anti-RT drugs was a nucleoside analog called 3 0 -azido-3 0 -deoxylthymidine (AZT) but the development of HIV strains resistant to this drug and others warrants the search for alternative RT inhibitors [1]. HIV protease is responsible for the maturation and production of infectious virions [2] and has also been a crucial target for anti-HIV drug development.…”

Section: Introductionmentioning

confidence: 99%