Interaction of β-L-2′,3′-dideoxy-2′,3′-didehydro-5-fluoro-CTP with human immunodeficiency virus-1 reverse transcriptase and human DNA polymerases:: Implications for human immunodeficiency virus drug design

被引:0
|
作者
Kukhanova, M
Li, XY
Chen, SH
King, I
Doyle, T
Prusoff, W
Cheng, YC
机构
[1] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA
[2] Vion Pharmaceut Inc, New Haven, CT 06511 USA
关键词
z;
D O I
暂无
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The work reported in this article has evaluated the relative molecular activity of the 5'-triphosphate of a novel beta-L-nucleoside with an unsaturated ribose residue, beta-L-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine (beta-L-Fd4CTP), with that of beta-L-2',3'-dideoxy-5-fluorocytidine (beta-L-FddCTP) and 2',3'-dideoxycytidine (ddCTP), on DNA strand elongation by human immunodeficiency virus-1 reverse transcriptase (HIV RT) and human DNA polymerases alpha (pol alpha), beta (pol beta), gamma (pol gamma), and epsilon (pol epsilon). The concentrations of beta-L-Fd4CTP that inhibited the yield of products by 50% were 0.20 mu M, 1.8 mu M, and 4.0 mu M for HIV RT, pol gamma, and pol beta, respectively. The beta-L-Fd4CTP at a concentration as high as 40 mu M had no inhibitory effect on pol epsilon, but could inhibit pol alpha by 10-20% at 20 mu M. The K-m and relative V-max values of beta-L-Fd4CTP, beta-L-FddCTP, and ddCTP for incorporation into the standing start point of 5'-[P-32]-oligonucleotide primer annealed with M13mp19 phage DNA by HIV RT and human DNA polymerases were evaluated. The efficiency of incorporation (V-max/K-m) of beta-L-Fd4CTP by HIV RT was about 4-fold and 12-fold higher than that of ddCTP and beta-L-FddCTP, respectively. In contrast, the V-max/K-m ratio of beta-L-Fd4CTP for pol gamma was 7-fold lower than that of ddCTP, but 4-fold higher than that of beta-L-FddCTP. Pol alpha could use beta-L-Fd4CTP as a substrate, but only at a high concentration (>20 mu M). Incorporation of beta-L-Fd4CTP by pol epsilon could not be detected. A hypothesis about the preferable recognition of the 2',3'-dideoxy-2',3'-didehydro-structure of beta-L-Fd4CTP to that of the 2',3'-dideoxy-structure of beta-L-FddCTP by HIV RT is discussed.
引用
收藏
页码:801 / 807
页数:7
相关论文
共 50 条
  • [1] SELECTIVE ACTION OF 2',3'-DIDEHYDRO-2',3'-DIDEOXYTHYMIDINE TRIPHOSPHATE ON HUMAN-IMMUNODEFICIENCY-VIRUS REVERSE-TRANSCRIPTASE AND HUMAN DNA-POLYMERASES
    HUANG, P
    FARQUHAR, D
    PLUNKETT, W
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1992, 267 (04) : 2817 - 2822
  • [2] The interaction of the reverse transcriptase of human immunodeficiency virus type 1 with 3'-terminally mispaired DNA
    Bakhanashvili, M
    Hizi, A
    [J]. ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1996, 334 (01) : 89 - 96
  • [3] INHIBITION OF HUMAN IMMUNODEFICIENCY VIRUS-1 REVERSE-TRANSCRIPTASE BY 3'-AZIDOTHYMIDINE TRIPHOSPHATE
    HEIDENREICH, O
    KRUHOFFER, M
    GROSSE, F
    ECKSTEIN, F
    [J]. EUROPEAN JOURNAL OF BIOCHEMISTRY, 1990, 192 (03): : 621 - 625
  • [4] EFFECTS OF THE 5'-TRIPHOSPHATE OF BETA-L-2',3'-DIDEOXY-5-FLUOROCYTIDINE (L-FDDC) ON HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE AND HUMAN DNA-POLYMERASES
    AGROFOGLIO, LA
    FARAJ, A
    WAKEFIELD, JK
    MCPHERSON, S
    MORROW, CD
    GOSSELIN, G
    IMBACH, JL
    SCHINAZI, RF
    SOMMADOSSI, JP
    [J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 1994, 208 : A40 - MEDI
  • [5] Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors
    Santos, Lucianna Helene
    Ferreira, Rafaela Salgado
    Caffarena, Ernesto Raul
    [J]. MEMORIAS DO INSTITUTO OSWALDO CRUZ, 2015, 110 (07): : 847 - 864
  • [6] A novel polymorphism at codon 333 of human immunodeficiency virus type 1 reverse transcriptase can facilitate dual resistance to zidovudine and L-2′,3′-dideoxy-3′-thiacytidine
    Kemp, SD
    Shi, CF
    Bloor, S
    Harrigan, PR
    Mellors, JW
    Larder, BA
    [J]. JOURNAL OF VIROLOGY, 1998, 72 (06) : 5093 - 5098
  • [7] CELLULAR PHARMACOLOGY OF 2',3'-DIDEOXY-2',3'-DIDEHYDROTHYMIDINE, A NUCLEOSIDE ANALOG ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS
    HO, HT
    HITCHCOCK, MJM
    [J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1989, 33 (06) : 844 - 849
  • [8] Design and synthesis of 2',3'-dideoxy-2',3'-didehydro-beta-L-cytidine (beta-L-d4C) and 2',3'-dideoxy-2',3'-didehydro-beta-L-5-fluorocytidine (beta-L-Fd4C), two exceptionally potent inhibitors of human hepatitis B virus (HBV) and potent inhibitors of human immunodeficiency virus (HIV) in vitro
    Lin, TS
    Luo, MZ
    Liu, MC
    Zhu, YL
    Gullen, E
    Dutschman, GE
    Cheng, YC
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (09) : 1757 - 1759
  • [9] DNA CHAIN TERMINATION ACTIVITY AND INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS REVERSE-TRANSCRIPTASE BY CARBOCYCLIC 2',3'-DIDEHYDRO-2',3'-DIDEOXYGUANOSINE TRIPHOSPHATE
    ORR, DC
    FIGUEIREDO, HT
    MO, CL
    PENN, CR
    CAMERON, JM
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1992, 267 (06) : 4177 - 4182
  • [10] In vitro selection and analysis of human immunodeficiency virus Type 1 resistant to derivatives of β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine
    Hammond, JL
    Parikh, UM
    Koontz, DL
    Schlueter-Wirtz, S
    Chu, CK
    Bazmi, HZ
    Schinazi, RF
    Mellors, JW
    [J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2005, 49 (09) : 3930 - 3932