Inhibitors of HIV-1 replication that inhibit HPV integrase

被引:218
作者
Robinson, WE
Reinecke, MG
AbdelMalek, S
Jia, Q
Chow, SA
机构
[1] UNIV CALIF IRVINE,DEPT MICROBIOL & MOLEC GENET,IRVINE,CA 92717
[2] TEXAS CHRISTIAN UNIV,DEPT CHEM,FT WORTH,TX 76129
[3] UNIV CALIF LOS ANGELES,DEPT MOL & MED PHARMACOL,LOS ANGELES,CA 90095
关键词
AIDS; therapeutics; natural products; chicoric acid;
D O I
10.1073/pnas.93.13.6326
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
HIV-1 replication depends on the viral enzyme integrase that mediates integration of a DNA copy of the virus into the host cell genome. This enzyme represents a novel target to which antiviral agents might he directed. Three compounds, 3,5-dicaffeoylquinic acid, 1-methoxyoxalyl-3,5-dicaffeoylquinic acid, and L-chicoric acid, inhibit HIV-1 integrase in biochemical assays at concentrations ranging front 0.06-0.66 mu g/ml; furthermore, these compounds inhibit HIV-1 replication in tissue culture at 1-4 mu g/ml. The toxic concentrations of these compounds are fully 100-fold greater than their antiviral concentrations, These compounds represent a potentially important new class of antiviral agents that may contribute to our understanding of the molecular mechanisms anisms of viral integration, Thus, the dicaffeoylquinic acids are promising leads to new anti-HIV therapeutics and offer a significant advance in the search for new HIV enzyme targets as they are both specific for HIV-1 integrase and active against HIV-1 in tissue culture.
引用
收藏
页码:6326 / 6331
页数:6
相关论文
共 41 条
[1]   HIV-1 INTEGRASE - HIGH-LEVEL PRODUCTION AND SCREENING ASSAY FOR THE ENDONUCLEOLYTIC ACTIVITY [J].
BILLICH, A ;
SCHAUER, M ;
FRANK, S ;
ROSENWIRTH, B ;
BILLICH, S .
ANTIVIRAL CHEMISTRY & CHEMOTHERAPY, 1992, 3 (02) :113-119
[2]   A NUCLEOPROTEIN COMPLEX MEDIATES THE INTEGRATION OF RETROVIRAL DNA [J].
BOWERMAN, B ;
BROWN, PO ;
BISHOP, JM ;
VARMUS, HE .
GENES & DEVELOPMENT, 1989, 3 (04) :469-478
[3]   RETROVIRAL INTEGRATION - STRUCTURE OF THE INITIAL COVALENT PRODUCT AND ITS PRECURSOR, AND A ROLE FOR THE VIRAL IN PROTEIN [J].
BROWN, PO ;
BOWERMAN, B ;
VARMUS, HE ;
BISHOP, JM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (08) :2525-2529
[4]   ASSOCIATION OF INTEGRASE, MATRIX, AND REVERSE-TRANSCRIPTASE ANTIGENS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 WITH VIRAL NUCLEIC-ACIDS FOLLOWING ACUTE INFECTION [J].
BUKRINSKY, MI ;
SHAROVA, N ;
MCDONALD, TL ;
PUSHKARSKAYA, T ;
TARPLEY, WG ;
STEVENSON, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (13) :6125-6129
[5]   DOMAINS OF THE INTEGRASE PROTEIN OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 RESPONSIBLE FOR POLYNUCLEOTIDYL TRANSFER AND ZINC-BINDING [J].
BUSHMAN, FD ;
ENGELMAN, A ;
PALMER, I ;
WINGFIELD, P ;
CRAIGIE, R .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (08) :3428-3432
[6]   HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INTEGRASE - EFFECT ON VIRAL REPLICATION OF MUTATIONS AT HIGHLY CONSERVED RESIDUES [J].
CANNON, PM ;
WILSON, W ;
BYLES, E ;
KINGSMAN, SM ;
KINGSMAN, AJ .
JOURNAL OF VIROLOGY, 1994, 68 (08) :4768-4775
[7]   A CHEMICAL-SCREENING STRATEGY FOR THE DEREPLICATION AND PRIORITIZATION OF HIV-INHIBITORY AQUEOUS NATURAL-PRODUCTS EXTRACTS [J].
CARDELLINA, JH ;
MUNRO, MHG ;
FULLER, RW ;
MANFREDI, KP ;
MCKEE, TC ;
TISCHLER, M ;
BOKESCH, HR ;
GUSTAFSON, KR ;
BEUTLER, JA ;
BOYD, MR .
JOURNAL OF NATURAL PRODUCTS, 1993, 56 (07) :1123-1129
[8]   INHIBITION OF THE IN-VITRO INTEGRATION OF MOLONEY MURINE LEUKEMIA-VIRUS DNA BY THE DNA MINOR-GROOVE BINDER NETROPSIN [J].
CARTEAU, S ;
MOUSCADET, JF ;
GOULAOUIC, H ;
SUBRA, F ;
AUCLAIR, C .
BIOCHEMICAL PHARMACOLOGY, 1994, 47 (10) :1821-1826
[9]   INHIBITORY EFFECT OF THE POLYANIONIC DRUG SURAMIN ON THE IN-VITRO HIV DNA INTEGRATION REACTION [J].
CARTEAU, S ;
MOUSCADET, JF ;
GOULAOUIC, H ;
SUBRA, F ;
AUCLAIR, C .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1993, 305 (02) :606-610
[10]   REVERSAL OF INTEGRATION AND DNA SPLICING MEDIATED BY INTEGRASE OF HUMAN-IMMUNODEFICIENCY-VIRUS [J].
CHOW, SA ;
VINCENT, KA ;
ELLISON, V ;
BROWN, PO .
SCIENCE, 1992, 255 (5045) :723-726