COMPETITIVE-INHIBITION OF HIV-1 PROTEASE BY WARFARIN DERIVATIVES

被引:51
作者
TUMMINO, PJ
FERGUSON, D
HUPE, D
机构
[1] Department of Biochemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor
关键词
D O I
10.1006/bbrc.1994.1700
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The oral anticoagulant warfarin (4-hydroxy-3-(3-oxo-1-phenylbutyl)-benzopyran-2-one) is a structurally novel low micromolar competitive inhibitor of HIV-1 protease in vitro. It was recently reported that warfarin inhibits HIV-1 infection in U-1 monocytes and viral production in ACH-2 lymphocytes (Bourinbaiar, A. S. et al., (1993) AIDS 7, 129-130.). Our results demonstrate that warfarin and a series of structurally related analogs inhibit the viral protease, the most potent analog having an IC50 = 1.9 mu M. Kinetic analysis reveals inhibition by warfarin occurs in a competitive manner, with K-i = 3.3 mu M. While it is unclear whether the cellular inhibition previously reported is due to inhibition of HIV-1 protease, the warfarin analogs are a novel class of nonpeptide HIV-1 protease inhibitors. (C) 1994 Academic Press, Inc.
引用
收藏
页码:290 / 294
页数:5
相关论文
共 20 条
[1]   EFFECT OF THE ORAL ANTICOAGULANT, WARFARIN, ON HIV-1 REPLICATION AND SPREAD [J].
BOURINBAIAR, AS ;
TAN, X ;
NAGORNY, R .
AIDS, 1993, 7 (01) :129-130
[2]  
BOURINBAIAR AS, 1993, ACTA VIROL, V37, P241
[3]   THE HIV-1 PROTEASE AS A THERAPEUTIC TARGET FOR AIDS [J].
DEBOUCK, C .
AIDS RESEARCH AND HUMAN RETROVIRUSES, 1992, 8 (02) :153-164
[4]  
FASCO MJ, 1982, J BIOL CHEM, V257, P1210
[5]   INHIBITION OF THE HIV-1 PROTEASE BY FULLERENE DERIVATIVES - MODEL-BUILDING STUDIES AND EXPERIMENTAL-VERIFICATION [J].
FRIEDMAN, SH ;
DECAMP, DL ;
SIJBESMA, RP ;
SRDANOV, G ;
WUDL, F ;
KENYON, GL .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1993, 115 (15) :6506-6509
[6]   CARBOXYLATED CALCIUM-BINDING PROTEINS AND VITAMIN-K [J].
GALLOP, PM ;
LIAN, JB ;
HAUSCHKA, PV .
NEW ENGLAND JOURNAL OF MEDICINE, 1980, 302 (26) :1460-1466
[7]   ORAL ANTICOAGULANTS - MECHANISM OF ACTION, CLINICAL EFFECTIVENESS, AND OPTIMAL THERAPEUTIC RANGE [J].
HIRSH, J ;
DALEN, JE ;
DEYKIN, D ;
POLLER, L .
CHEST, 1992, 102 (04) :S312-S326
[8]   HIV PROTEASE - A NOVEL CHEMOTHERAPEUTIC TARGET FOR AIDS [J].
HUFF, JR .
JOURNAL OF MEDICINAL CHEMISTRY, 1991, 34 (08) :2305-2314
[9]  
JORDAN SP, 1992, J BIOL CHEM, V267, P20028
[10]   SYMMETRY-BASED INHIBITORS OF HIV PROTEASE - STRUCTURE ACTIVITY STUDIES OF ACYLATED 2,4-DIAMINO-1,5-DIPHENYL-3-HYDROXYPENTANE AND 2,5-DIAMINO-1,6-DIPHENYLHEXANE-3,4-DIOL [J].
KEMPF, DJ ;
CODACOVI, L ;
WANG, XC ;
KOHLBRENNER, WE ;
WIDEBURG, NE ;
SALDIVAR, A ;
VASAVANONDA, S ;
MARSH, KC ;
BRYANT, P ;
SHAM, HL ;
GREEN, BE ;
BETEBENNER, DA ;
ERICKSON, J ;
NORBECK, DW .
JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (03) :320-330