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 journalArticle

5 Citations (Scopus)

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

Fingerprint

Nucleotides
Derivatives
Adenosine
Kinetics
HIV-1
Diphosphates
Scaffolds
HIV
Substrates
Enzymes
Pharmaceutical Preparations
Human immunodeficiency virus 1 reverse transcriptase
2'-deoxyadenosine triphosphate

Keywords

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

ASJC Scopus subject areas

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

Cite this

Pre-steady state kinetic analysis of cyclobutyl derivatives of 2′-deoxyadenosine 5′-triphosphate as inhibitors of HIV-1 reverse transcriptase. / Kim, Jiae; Wang, Ligong; Li, Yongfeng; Becnel, Kimberlynne D.; Frey, Kathleen M.; Garforth, Scott J.; Prasad, Vinayaka R.; Schinazi, Raymond F.; Liotta, Dennis C.; Anderson, Karen S.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 22, No. 12, 15.06.2012, p. 4064-4067.

Research output: Contribution to journalArticle

Kim, Jiae ; Wang, Ligong ; Li, Yongfeng ; Becnel, Kimberlynne D. ; Frey, Kathleen M. ; Garforth, Scott J. ; Prasad, Vinayaka R. ; Schinazi, Raymond F. ; Liotta, Dennis C. ; Anderson, Karen S. / Pre-steady state kinetic analysis of cyclobutyl derivatives of 2′-deoxyadenosine 5′-triphosphate as inhibitors of HIV-1 reverse transcriptase. In: Bioorganic and Medicinal Chemistry Letters. 2012 ; Vol. 22, No. 12. pp. 4064-4067.
@article{35832d9f66d0413eb01f34147aca2c2e,
title = "Pre-steady state kinetic analysis of cyclobutyl derivatives of 2′-deoxyadenosine 5′-triphosphate as inhibitors of HIV-1 reverse transcriptase",
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.",
keywords = "Cyclobutyl adenosine analogs, HIV-1 RT, K65R mutant of RT, Pre-steady state kinetics, Tenofovir",
author = "Jiae Kim and Ligong Wang and Yongfeng Li and Becnel, {Kimberlynne D.} and Frey, {Kathleen M.} and Garforth, {Scott J.} and Prasad, {Vinayaka R.} and Schinazi, {Raymond F.} and Liotta, {Dennis C.} and Anderson, {Karen S.}",
year = "2012",
month = "6",
day = "15",
doi = "10.1016/j.bmcl.2012.04.078",
language = "English (US)",
volume = "22",
pages = "4064--4067",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "12",

}

TY - JOUR

T1 - Pre-steady state kinetic analysis of cyclobutyl derivatives of 2′-deoxyadenosine 5′-triphosphate as inhibitors of HIV-1 reverse transcriptase

AU - Kim, Jiae

AU - Wang, Ligong

AU - Li, Yongfeng

AU - Becnel, Kimberlynne D.

AU - Frey, Kathleen M.

AU - Garforth, Scott J.

AU - Prasad, Vinayaka R.

AU - Schinazi, Raymond F.

AU - Liotta, Dennis C.

AU - Anderson, Karen S.

PY - 2012/6/15

Y1 - 2012/6/15

N2 - 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.

AB - 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.

KW - Cyclobutyl adenosine analogs

KW - HIV-1 RT

KW - K65R mutant of RT

KW - Pre-steady state kinetics

KW - Tenofovir

UR - http://www.scopus.com/inward/record.url?scp=84861574063&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861574063&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2012.04.078

DO - 10.1016/j.bmcl.2012.04.078

M3 - Article

C2 - 22595174

AN - SCOPUS:84861574063

VL - 22

SP - 4064

EP - 4067

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 12

ER -