Pre-steady state kinetic analysis of cyclobutyl derivatives of 2′-deoxyadenosine 5′-triphosphate as inhibitors of HIV-1 reverse transcriptase

Jiae Kim, Ligong Wang, Yongfeng Li, Kimberlynne D. Becnel, Kathleen M. Frey, Scott J. Garforth, Vinayaka R. Prasad, Raymond F. Schinazi, Dennis C. Liotta, Karen S. Anderson

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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 RTWT. 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 RTK65R. These results demonstrate cyclobutyl adenosine analogs can act as substrates for incorporation by HIV-1 RT and be a potential scaffold for HIV inhibitors.

Original languageEnglish (US)
Pages (from-to)4064-4067
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number12
DOIs
Publication statusPublished - Jun 15 2012

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Keywords

  • Cyclobutyl adenosine analogs
  • HIV-1 RT
  • K65R mutant of RT
  • Pre-steady state kinetics
  • Tenofovir

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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