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

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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
StatePublished - Jun 15 2012

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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