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Author Notes:

Karen S. Anderson, Yale University School of Medicine, Dept. of Pharmacology, SHM B350B, 333 Cedar Street, New Haven, CT 06520-8066. Tel.: 203-785-4526; Fax: 203-785-7670; karen.anderson@yale.edu.

We would like to thank Dr. Stephen Hughes, Dr. Paul Boyer and Dr. Andrea Ferris (NIH) for the HIV-1 RTWT clone.

We would also like to acknowledge Sierra Bioresearch (Tucson, AZ) for synthesizing compound 4.

Subjects:

Research Funding:

We would also like to thank the National Institutes of Health for support to GM49551 to K.S.A.

RFS is supported by CFAR NIH grant 2P30-AI-050409 and the Department of Veterans Affairs.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Physical Sciences
  • Chemistry, Medicinal
  • Chemistry, Organic
  • Pharmacology & Pharmacy
  • Chemistry
  • HIV-1 RT
  • Cyclobutyl adenosine analogs
  • Tenofovir
  • K65R mutant of RT
  • Pre-steady state kinetics
  • K65R
  • RESISTANCE
  • MUTATIONS
  • TENOFOVIR

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

Tools:

Journal Title:

Bioorganic and Medicinal Chemistry Letters

Volume:

Volume 22, Number 12

Publisher:

, Pages 4064-4067

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Pre-steady state kinetic analysis was utilized for biochemical evaluation of a series of cyclobutyl adenosine nucleotide analogs with HIV-1 RTWT. 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.

Copyright information:

© 2012 Elsevier Ltd. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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