INHIBITION OF HIV-1 INFECTIVITY BY ZINC-EJECTING AROMATIC C-NITROSO COMPOUNDS

被引:206
作者
RICE, WG
SCHAEFFER, CA
HARTEN, B
VILLINGER, F
SOUTH, TL
SUMMERS, MF
HENDERSON, LE
BESS, JW
ARTHUR, LO
MCDOUGAL, JS
ORLOFF, SL
MENDELEYEV, J
KUN, E
机构
[1] NCI,FREDERICK CANC RES & DEV CTR,PROGRAM RESOURCES INC DYNCORP,AIDS VACCINE PROGRAM,FREDERICK,MD 21702
[2] EMORY UNIV,SCH MED,DEPT PATHOL & LAB MED,ATLANTA,GA 30322
[3] CTR DIS CONTROL,NCID,DHA,IMMUNOL BRANCH,ATLANTA,GA 30333
[4] OCTAMER INC,TIBURON,CA 94920
[5] SAN FRANCISCO STATE UNIV,ROMBERG TIBURON CTR,ENVIRONM TOXICOL & CHEM LAB,TIBURON,CA 94920
关键词
D O I
10.1038/361473a0
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
RETROVIRAL nucleocapsid and gag-precursor proteins from all known strains of retroviruses contain one or two copies of an invariant sequence, Cys-X2-Cys-X4-His-X4-Cys1,2, that is populated with zinc in mature particles3. Modification of cysteine or histidine residues results in defective packaging of genomic viral RNA and formation of non-infectious particles4-8, making these structures potentially attractive targets for antiviral therapy3,8. We recently reported that aromatic C-nitroso ligands of poly(ADP-ribose) polymerase preferentially destabilize one of the two (CYS-X2-CYS-X28-His-X2-Cys) zinc-fingers with concomitant loss of enzymatic activity9,10, coincidental with selective cytocidal action of the C-nitroso substituted ligands on cancer cells11. Based on the occurrence of (3Cys, 1His) zinc-binding sites in both retroviral nucleocapsid and gag proteins and in poly(ADP-ribose) polymerase12, we reasoned that the C-nitroso compounds may also have antiretroviral effects. We show here that two such compounds, 3-nitrosobenzamide and 6-nitroso-1,2-benzopyrone, inhibit infection of human immunodeficiency virus HIV-1 in human lymphocytes and also eject zinc from isolated HIV-1 nucleocapsid zinc fingers and from intact HIV-1 virions. Thus the design of zinc-ejecting agents that target retroviral zinc fingers represents a new approach to the chemotherapy of AIDS.
引用
收藏
页码:473 / 475
页数:3
相关论文
共 34 条
  • [1] MUTATIONS OF RNA AND PROTEIN SEQUENCES INVOLVED IN HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PACKAGING RESULT IN PRODUCTION OF NONINFECTIOUS VIRUS
    ALDOVINI, A
    YOUNG, RA
    [J]. JOURNAL OF VIROLOGY, 1990, 64 (05) : 1920 - 1926
  • [2] TIGHTLY BOUND ZINC IN HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1, HUMAN T-CELL LEUKEMIA-VIRUS TYPE-I, AND OTHER RETROVIRUSES
    BESS, JW
    POWELL, PJ
    ISSAQ, HJ
    SCHUMACK, LJ
    GRIMES, MK
    HENDERSON, LE
    ARTHUR, LO
    [J]. JOURNAL OF VIROLOGY, 1992, 66 (02) : 840 - 847
  • [3] A STUDY OF THE DIMER FORMATION OF ROUS-SARCOMA VIRUS-RNA AND OF ITS EFFECT ON VIRAL PROTEIN-SYNTHESIS INVITRO
    BIETH, E
    GABUS, C
    DARLIX, JL
    [J]. NUCLEIC ACIDS RESEARCH, 1990, 18 (01) : 119 - 127
  • [4] DESTABILIZATION OF ZN2+ COORDINATION IN ADP-RIBOSE TRANSFERASE (POLYMERIZING) BY 6-NITROSO-1,2-BENZOPYRONE COINCIDENTAL WITH INACTIVATION OF THE POLYMERASE BUT NOT THE DNA-BINDING FUNCTION
    BUKI, KG
    BAUER, PI
    MENDELEYEV, J
    HAKAM, A
    KUN, E
    [J]. FEBS LETTERS, 1991, 290 (1-2) : 181 - 185
  • [5] EXTENDED X-RAY ABSORPTION FINE-STRUCTURE STUDIES OF A RETROVIRUS - EQUINE INFECTIOUS-ANEMIA VIRUS CYSTEINE ARRAYS ARE COORDINATED TO ZINC
    CHANCE, MR
    SAGI, I
    WIRT, MD
    FRISBIE, SM
    SCHEURING, E
    CHEN, E
    BESS, JW
    HENDERSON, LE
    ARTHUR, LO
    SOUTH, TL
    PEREZALVARADO, G
    SUMMERS, MF
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (21) : 10041 - 10045
  • [6] CHEN MJ, 1980, P NATL ACAD SCI USA, V77, P4961
  • [7] INHIBITION OF HIV-1-IIIB REPLICATION IN AA-2 AND MT-2 CELLS IN CULTURE BY 2 LIGANDS OF POLY (ADP-RIBOSE) POLYMERASE - 6-AMINO-1,2-BENZOPYRONE AND 5-IODO-6-AMINO-1,2-BENZOPYRONE
    COLE, GA
    BAUER, G
    KIRSTEN, E
    MENDELEYEV, J
    BAUER, PI
    BUKI, KG
    HAKAM, A
    KUN, E
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1991, 180 (02) : 504 - 514
  • [8] CORNILLE F, 1990, INT J PEPT PROT RES, V36, P551
  • [9] POINT MUTATIONS IN THE PROXIMAL CYS-HIS BOX OF ROUS-SARCOMA VIRUS NUCLEOCAPSID PROTEIN
    DUPRAZ, P
    OERTLE, S
    MERIC, C
    DAMAY, P
    SPAHR, PF
    [J]. JOURNAL OF VIROLOGY, 1990, 64 (10) : 4978 - 4987
  • [10] PHYSICOCHEMICAL PROPERTIES OF CLONED NUCLEOCAPSID PROTEIN FROM HIV - INTERACTIONS WITH METAL-IONS
    FITZGERALD, DW
    COLEMAN, JE
    [J]. BIOCHEMISTRY, 1991, 30 (21) : 5195 - 5201