Unique metabolism of a novel antiviral L-nucleoside analog, 2′-fluoro-5-methyl-β-L-arabinofuranosyluracil:: a substrate for both thymidine kinase and deoxycytidine kinase

被引:49
作者
Liu, SH [1 ]
Grove, KL [1 ]
Cheng, YC [1 ]
机构
[1] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA
关键词
D O I
10.1128/AAC.42.4.833
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
2'-Fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU) is the first L-nucleoside analog with low cytotoxicity discovered to have potent antiviral activities against both hepatitis B virus and Epstein-Barr virus but not human immunodeficiency virus. This spectrum of activity is different from those of the other L-nucleoside analogs examined. L-FMAU enters cells through equilibrative-sensitive and -insensitive nucleoside transport as well as through nonfacilitated passive diffusion. L-FMAU is phosphorylated stepwise in cells to its mono-, di-, and triphosphate forms. In the present study the enzymes responsible for the first step of L-FMAU phosphorylation were identified. This is the first thymidine analog shown to be a substrate not only for cytosolic thymidine kinase and mitochondrial deoxypyrimidine kinase but also for deoxycytidine kinase. This finding suggests that the antiviral activity of L-FMAU will not be limited by the loss or alteration of any of these deoxynucleoside kinases.
引用
收藏
页码:833 / 839
页数:7
相关论文
共 30 条
[1]  
Ayoola E. A., 1988, Bull. World Health Org, V66, P443
[2]  
BRIDGES EG, 1996, PROG LIV DIS, V13, P231
[3]  
CHANG CN, 1992, J BIOL CHEM, V267, P13938
[4]   HUMAN DEOXYCYTIDINE KINASE - PURIFICATION AND CHARACTERIZATION OF CYTOPLASMIC AND MITOCHONDRIAL ISOZYMES DERIVED FROM BLAST CELLS OF ACUTE MYELOCYTIC-LEUKEMIA PATIENTS [J].
CHENG, YC ;
DOMIN, B ;
LEE, LS .
BIOCHIMICA ET BIOPHYSICA ACTA, 1977, 481 (02) :481-492
[5]   DIFFERENTIAL ACTIVITY OF POTENTIAL ANTI-VIRAL NUCLEOSIDE ANALOGS ON HERPES-SIMPLEX VIRUS-INDUCED AND HUMAN CELLULAR THYMIDINE KINASES [J].
CHENG, YC ;
DUTSCHMAN, G ;
FOX, JJ ;
WATANABE, KA ;
MACHIDA, H .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1981, 20 (03) :420-423
[6]  
CHOU TC, 1982, CANCER RES, V42, P3957
[7]   USE OF 2'-FLUORO-5-METHYL-BETA-L-ARABINOFURANOSYLURACIL AS A NOVEL ANTIVIRAL AGENT FOR HEPATITIS-B VIRUS AND EPSTEIN-BARR-VIRUS [J].
CHU, CK ;
MA, TW ;
SHANHMUGANATHAN, K ;
WANG, CG ;
XIANG, YJ ;
PAI, SB ;
YAO, GQ ;
SOMMADOSSI, JP ;
CHENG, YC .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1995, 39 (04) :979-981
[8]   BINDING OF NITROBENZYLTHIOINOSINE TO HIGH-AFFINITY SITES ON THE NUCLEOSIDE-TRANSPORT MECHANISM OF HELA-CELLS [J].
DAHLIGHARLEY, E ;
EILAM, Y ;
PATERSON, ARP ;
CASS, CE .
BIOCHEMICAL JOURNAL, 1981, 200 (02) :295-305
[9]   INHIBITION OF THE REPLICATION OF HEPATITIS-B VIRUS INVITRO BY 2',3'-DIDEOXY-3'-THIACYTIDINE AND RELATED ANALOGS [J].
DOONG, SL ;
TSAI, CH ;
SCHINAZI, RF ;
LIOTTA, DC ;
CHENG, YC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (19) :8495-8499
[10]   THE ANTI-HEPATITIS-B VIRUS ACTIVITIES, CYTOTOXICITIES, AND ANABOLIC PROFILES OF THE (-) AND (+) ENANTIOMERS OF CIS-5-FLUORO-1-[2-(HYDROXYMETHYL)-1,3-OXATHIOLAN-5-YL]CYTOSINE [J].
FURMAN, PA ;
DAVIS, M ;
LIOTTA, DC ;
PAFF, M ;
FRICK, LW ;
NELSON, DJ ;
DORNSIFE, RE ;
WURSTER, JA ;
WILSON, LJ ;
FYFE, JA ;
TUTTLE, JV ;
MILLER, WH ;
CONDREAY, L ;
AVERETT, DR ;
SCHINAZI, RF ;
PAINTER, GR .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1992, 36 (12) :2686-2692