Abstract
Pre-steady state kinetic analysis was utilized for biochemical evaluation of a series of cyclobutyl adenosine nucleotide analogs with HIV-1 RT(WT). The phosphonyl-diphosphate form of the cyclobutyl nucleotide, 5, was the most efficiently incorporated of the series. Nucleotide 5 was fourfold more efficiently incorporated than the FDA approved TFV-DP by RT(WT). The kinetics of incorporation for 5 using the drug resistant mutant enzyme K65R was also determined. Compound 5 was threefold more efficiently incorporated compared to TFV-DP with RT(K65R). These results demonstrate cyclobutyl adenosine analogs can act as substrates for incorporation by HIV-1 RT and be a potential scaffold for HIV inhibitors.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenine / analogs & derivatives
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Adenine / pharmacology
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Anti-HIV Agents / chemical synthesis*
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Anti-HIV Agents / pharmacology
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Cyclobutanes / chemical synthesis*
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Cyclobutanes / pharmacology
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DNA Primers
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Deoxyadenine Nucleotides / chemical synthesis*
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Deoxyadenine Nucleotides / pharmacology
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Drug Resistance, Viral / drug effects
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Drug Resistance, Viral / genetics
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HIV Reverse Transcriptase / antagonists & inhibitors*
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HIV Reverse Transcriptase / chemistry
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HIV Reverse Transcriptase / genetics
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HIV-1 / drug effects*
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HIV-1 / genetics
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Humans
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Kinetics
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Mutation
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Nucleic Acid Amplification Techniques
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Organophosphonates / pharmacology
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Reverse Transcriptase Inhibitors / chemical synthesis*
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Reverse Transcriptase Inhibitors / pharmacology
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Tenofovir
Substances
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Anti-HIV Agents
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Cyclobutanes
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DNA Primers
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Deoxyadenine Nucleotides
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Organophosphonates
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Reverse Transcriptase Inhibitors
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Tenofovir
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reverse transcriptase, Human immunodeficiency virus 1
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HIV Reverse Transcriptase
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Adenine
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2'-deoxyadenosine triphosphate