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

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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 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

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

UN SDGs

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

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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

Keywords

ASJC Scopus subject areas

UN SDGs

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