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

doi:10.1016/j.bmcl.2012.04.078

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 journal › Article › peer-review

8 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 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.

Original language	English (US)
Pages (from-to)	4064-4067
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	12
DOIs	https://doi.org/10.1016/j.bmcl.2012.04.078
State	Published - Jun 15 2012

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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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10.1016/j.bmcl.2012.04.078

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Kim, J., Wang, L., Li, Y., Becnel, K. D., Frey, K. M., Garforth, S. J., Prasad, V. R., Schinazi, R. F., Liotta, D. C., & Anderson, K. S. (2012). Pre-steady state kinetic analysis of cyclobutyl derivatives of 2′-deoxyadenosine 5′-triphosphate as inhibitors of HIV-1 reverse transcriptase. Bioorganic and Medicinal Chemistry Letters, 22(12), 4064-4067. https://doi.org/10.1016/j.bmcl.2012.04.078

Kim, J, Wang, L, Li, Y, Becnel, KD, Frey, KM, Garforth, SJ, Prasad, VR, Schinazi, RF, Liotta, DC & Anderson, KS 2012, 'Pre-steady state kinetic analysis of cyclobutyl derivatives of 2′-deoxyadenosine 5′-triphosphate as inhibitors of HIV-1 reverse transcriptase', Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 12, pp. 4064-4067. https://doi.org/10.1016/j.bmcl.2012.04.078

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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.\}",

note = "Funding Information: We would like to thank Drs. Stephen Hughes, Paul Boyer and Andrea Ferris (NIH) for the HIV-1 RT WT clone. We would also like to acknowledge Sierra Bioresearch (Tucson, AZ) for synthesizing compound 4 . 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. ",

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doi = "10.1016/j.bmcl.2012.04.078",

language = "English (US)",

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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.

N1 - Funding Information: We would like to thank Drs. Stephen Hughes, Paul Boyer and Andrea Ferris (NIH) for the HIV-1 RT WT clone. We would also like to acknowledge Sierra Bioresearch (Tucson, AZ) for synthesizing compound 4 . 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.

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

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

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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