Probing the molecular mechanism of action of the HIV-1 reverse transcriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) using pre-steady-state kinetics

被引：16

作者：

Muftuoglu, Yagmur ^{[1
]}

Sohl, Christal D. ^{[1
]}

Mislak, Andrea C. ^{[1
]}

Mitsuya, Hiroaki ^{[2
,3
,4
]}

Sarafianos, Stefan G. ^{[5
,6
,7
]}

Anderson, Karen S. ^{[1
]}

机构：

[1] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA

[2] Kumamoto Univ, Grad Sch Med Sci, Dept Infect Dis, Kumamoto 8608556, Japan

[3] Kumamoto Univ, Grad Sch Med Sci, Dept Hematol, Kumamoto 8608556, Japan

[4] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA

[5] Univ Missouri, Sch Med, CS Bond Life Sci Ctr, Columbia, MO 65211 USA

[6] Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, Columbia, MO 65211 USA

[7] Univ Missouri, Sch Med, Dept Biochem, Columbia, MO 65211 USA

来源：

ANTIVIRAL RESEARCH | 2014年 / 106卷

关键词：

HIV; Reverse transcriptase; Enzyme kinetics; EFdA; Polymerase; IMMUNODEFICIENCY-VIRUS TYPE-1; MITOCHONDRIAL-DNA POLYMERASE; HOST TOXICITY; 4'-ETHYNYL-2-FLUORO-2'-DEOXYADENOSINE; GAMMA; DISCRIMINATION; NUCLEOTIDE; ENTECAVIR; SUBSTRATE; FIDELITY;

D O I：

10.1016/j.antiviral.2014.03.001

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The novel antiretroviral 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a potent nucleoside HIV-1 reverse transcriptase (RT) inhibitor (NRTI). Unlike other FDA-approved NRTIs, EFdA contains a 3'-hydroxyl. Pre-steady-state kinetics showed RT preferred incorporating EFdA-TP over native dATP. Moreover, RT slowly inserted nucleotides past an EFdA-terminated primer, resulting in delayed chain termination with unaffected fidelity. This is distinct from KP1212, another 3'-hydroxyl-containing RT inhibitor considered to promote viral lethal mutagenesis. New mechanistic features of RI inhibition by EFdA are revealed. (C) 2014 Elsevier B.V. All rights reserved.

引用

页码：1 / 4

页数：4

共 24 条

[1] Mitochondrial interference by anti-HIV drugs: mechanisms beyond Pol-γ inhibition
Apostolova, Nadezda
Blas-Garcia, Ana
Esplugues, Juan V.
[J]. TRENDS IN PHARMACOLOGICAL SCIENCES, 2011, 32 (12) : 715 - 725
[2] Pre-steady-state kinetic studies establish entecavir 5′-triphosphate as a substrate for HIV-1 reverse transcriptase
Domaoal, Robert A.
McMahon, Moira
Thio, Chloe L.
Bailey, Christopher M.
Tirado-Rives, Julian
Obikhod, Aleksander
Detorio, Mervi
Rapp, Kimberly L.
Siliciano, Robert F.
Schinazi, Raymond F.
Anderson, Karen S.
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (09) : 5452 - 5459
[3] Mechanistic studies comparing the incorporation of (+) and (-) isomers of 3TCTP by HIV-1 reverse transcriptase
Feng, JY
Anderson, KS
[J]. BIOCHEMISTRY, 1999, 38 (01) : 55 - 63
[4] KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis
Harris, KS
Brabant, W
Styrchak, S
Gall, A
Daifuku, R
[J]. ANTIVIRAL RESEARCH, 2005, 67 (01) : 1 - 9
[5] Understanding the molecular mechanism of sequence dependent Tenofovir removal by HIV-1 reverse transcriptase: Differences in primer binding site versus polypurine tract
Iyidogan, Pinar
Anderson, Karen S.
[J]. ANTIVIRAL RESEARCH, 2012, 95 (02) : 93 - 103
[6] Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase
Johnson, AA
Ray, AS
Hanes, J
Suo, ZC
Colacino, JM
Anderson, KS
Johnson, KA
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (44) : 40847 - 40857
[7] Role of induced Fit in Limiting Discrimination against AZT by HIV Reverse Transcriptase
Kellinger, Matthew W.
Johnson, Kenneth A.
[J]. BIOCHEMISTRY, 2011, 50 (22) : 5008 - 5015
[8] RNA dependent DNA replication fidelity of HIV-1 reverse transcriptase: Evidence of discrimination between DNA and RNA substrates
Kerr, SG
Anderson, KS
[J]. BIOCHEMISTRY, 1997, 36 (46) : 14056 - 14063
[9] Nucleocapsid Protein Annealing of a Primer-Template Enhances (+)-Strand DNA Synthesis and Fidelity by HIV-1 Reverse Transcriptase
Kim, Jiae
Roberts, Anne
Yuan, Hua
Xiong, Yong
Anderson, Karen S.
[J]. JOURNAL OF MOLECULAR BIOLOGY, 2012, 415 (05) : 866 - 880
[10] THE SUGAR RING CONFORMATION OF 4′-ETHYNYL-2-FLUORO-2′-DEOXYADENOSINE AND ITS RECOGNITION BY THE POLYMERASE ACTIVE SITE OF HIV REVERSE TRANSCRIPTASE
Kirby, K. A.
Singh, K.
Michailidis, E.
Marchand, B.
Kodama, E. N.
Ashida, N.
Mitsuya, H.
Parniak, M. A.
Sarafianos, S. G.
[J]. CELLULAR AND MOLECULAR BIOLOGY, 2011, 57 (01) : 40 - 46

← 1 2 3 →