E5531, A PURE ENDOTOXIN ANTAGONIST OF HIGH POTENCY

被引:291
作者
CHRIST, WJ
ASANO, O
ROBIDOUX, ALC
PEREZ, M
WANG, YA
DUBUC, GR
GAVIN, WE
HAWKINS, LD
MCGUINNESS, PD
MULLARKEY, MA
LEWIS, MD
KISHI, Y
KAWATA, T
BRISTOL, JR
ROSE, JR
ROSSIGNOL, DP
KOBAYASHI, S
HISHINUMA, L
KIMURA, A
ASAKAWA, N
KATAYAMA, K
YAMATSU, I
机构
[1] EISAI RES INST, ANDOVER, MA 01810 USA
[2] EISAI & CO LTD, TSUKUBA RES LABS, TSUKUBA, IBARAKI 30026, JAPAN
关键词
D O I
10.1126/science.7701344
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
Shock due to Gram-negative bacterial sepsis is a consequence of acute inflammatory response to lipopolysaccharide (LPS) or endotoxin released from bacteria. LPS is a major constituent of the outer membrane of Gram-negative bacteria, and its terminal disaccharide phospholipid (lipid A) portion contains the key structural features responsible for toxic activity. Based on the proposed structure of nontoxic Rhodobacter capsulatus lipid A, a fully stabilized endotoxin antagonist E5531 has been synthesized. In vitro, E5531 demonstrated potent antagonism of LPS-mediated cellular activation in a variety of systems. In vivo, E5531 protected mice from LPS-induced lethality and, in cooperation with an antibiotic, protected mice from a lethal infection of viable Escherichia coli.
引用
收藏
页码:80 / 83
页数:4
相关论文
共 33 条
[1]   CYTOKINES AND THEIR INTERACTIONS WITH OTHER INFLAMMATORY MEDIATORS IN THE PATHOGENESIS OF SEPSIS AND SEPTIC SHOCK [J].
BILLIAU, A ;
VANDEKERCKHOVE, F .
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, 1991, 21 (06) :559-573
[2]   GRAM-NEGATIVE SEPSIS - A DILEMMA OF MODERN MEDICINE [J].
BONE, RC .
CLINICAL MICROBIOLOGY REVIEWS, 1993, 6 (01) :57-68
[3]   GRAM-NEGATIVE SEPSIS - BACKGROUND, CLINICAL-FEATURES, AND INTERVENTION [J].
BONE, RC .
CHEST, 1991, 100 (03) :802-808
[4]  
BULAWA CE, 1984, J BIOL CHEM, V259, P4846
[5]  
BUNNELL E, 1995, 24TH ED SCI S SOC CR
[6]   TOTAL SYNTHESIS OF THE PROPOSED STRUCTURE OF RHODOBACTER-SPHAEROIDES LIPID-A RESULTING IN SYNTHESIS OF NEW POTENT LIPOPOLYSACCHARIDE ANTAGONISTS [J].
CHRIST, WJ ;
MCGUINNESS, PD ;
ASANO, O ;
WANG, Y ;
MULLARKEY, MA ;
PEREZ, M ;
HAWKINS, LD ;
BLYTHE, TA ;
DUBUC, GR ;
ROBIDOUX, AL .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1994, 116 (08) :3637-3638
[7]  
CHRIST WJ, 1836, Patent No. 935050
[8]  
CHRIST WJ, UNPUB
[9]   ANTIBIOTIC-INDUCED RELEASE OF ENDOTOXIN FROM BACTERIA IN-VITRO [J].
CROSBY, HA ;
BION, JF ;
PENN, CW ;
ELLIOTT, TSJ .
JOURNAL OF MEDICAL MICROBIOLOGY, 1994, 40 (01) :23-30
[10]   ANTIENDOTOXIN ACTIVITY OF LIPID-A ANALOGS - REQUIREMENTS OF THE CHEMICAL-STRUCTURE [J].
DANNER, RL ;
VANDERVORT, AL ;
DOERFLER, ME ;
STUETZ, P ;
PARRILLO, JE .
PHARMACEUTICAL RESEARCH, 1990, 7 (03) :260-263