RFI-641 inhibits entry of respiratory syncytial virus via interactions with fusion protein

被引:61
作者
Razinkov, V
Gazumyan, A
Nikitenko, A
Ellestad, G
Krishnamurthy, G [1 ]
机构
[1] Wyeth Ayerst Res, Dept Biol Chem, Pearl River, NY 10965 USA
[2] Wyeth Ayerst Res, Dept Infect Dis Res, Pearl River, NY 10965 USA
[3] Wyeth Ayerst Res, Dept Chem Sci, Pearl River, NY 10965 USA
来源
CHEMISTRY & BIOLOGY | 2001年 / 8卷 / 07期
关键词
respiratory syncytial virus; entry; attachment; fusion; inhibition; fusion protein; dequenching assay;
D O I
10.1016/S1074-5521(01)00042-4
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
Background: R171-641, a small dendrimer-like compound, is a potent and selective inhibitor of respiratory syncytial virus (RSV), which is currently a clinical candidate for the treatment of upper and lower respiratory tract infections caused by RSV. RFI-641 inhibits RSV growth with an IC50 value of 50 nM and prevents syncytia formation in tissue culture. RSV contains of three surface glycoproteins, a small hydrophobic (SH) protein of unknown function, and attachment (G) and fusion (F) proteins that enable binding and fusion of virus, respectively, with target cells. Because of their role in attachment and fusion, the G and F surface proteins are prominent targets for therapeutic intervention. RFI-641 was previously shown to bind purified preparations of RSV fusion protein. Based on this observation, in conjunction with the biological results, it was speculated that the fusion event might be the target of these inhibitors. Results: A fusion assay based upon the relief of self-quenching of octadecyl rhodamine R18 was used to determine effects of the inhibitors on binding and fusion of RSV. The results show that RFI-641 inhibits both RSV-cell binding and fusion events. The inhibition of RSV is mediated via binding to the fusion protein on the viral surface. A closely related analog, WAY-158830, which is much less active in the virus-infectivity assay does not inhibit binding and fusion of RSV with Vero cells. Conclusions: RFI-641, an in vivo active RSV inhibitor, is shown to inhibit both binding and fusion of RSV with cells, events that are early committed steps in RSV entry and pathogenicity. The results described here demonstrate that a non-peptidic, small molecule can inhibit binding and fusion of enveloped virus specifically via interaction with the viral fusion protein. (C) 2001 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:645 / 659
页数:15
相关论文
共 26 条
[1]  
Aulabaugh Ann, 2000, Drugs of the Future, V25, P287, DOI 10.1358/dof.2000.025.03.572014
[2]  
BLUMENTHAL R, 1987, J BIOL CHEM, V262, P13614
[3]  
Collins P.L., 1996, FIELDS VIROLOGY, V3, P1313
[4]  
COLLINS PL, 1991, PARAMYXOVIRUSES, P103
[5]  
DELIMA MDP, 1992, EUR J BIOCHEM, V205, P181
[6]   Novel and specific respiratory syncytial virus inhibitors that target virus fusion [J].
Ding, WD ;
Mitsner, B ;
Krishnamurthy, G ;
Aulabaugh, A ;
Hess, CD ;
Zaccardi, J ;
Cutler, M ;
Feld, B ;
Gazumyan, A ;
Raifeld, Y ;
Nikitenko, A ;
Lang, SA ;
Gluzman, Y ;
O'Hara, B ;
Ellestad, GA .
JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (15) :2671-2675
[7]   ENTRY INTO HOST-CELLS OF SINDBIS VIRUS, VESICULAR STOMATITIS-VIRUS AND SENDAI VIRUS [J].
FAN, DP ;
SEFTON, BM .
CELL, 1978, 15 (03) :985-992
[8]   Identification of a linear heparin binding domain for human respiratory syncytial virus attachment glycoprotein G [J].
Feldman, SA ;
Hendry, RM ;
Beeler, JA .
JOURNAL OF VIROLOGY, 1999, 73 (08) :6610-6617
[9]   Novel anti-RSV dianionic dendrimer-like compounds: Design, synthesis and biological evaluation [J].
Gazumyan, A ;
Mitsner, B ;
Ellestad, GA .
CURRENT PHARMACEUTICAL DESIGN, 2000, 6 (05) :525-546
[10]   PROSPECTS FOR A RESPIRATORY SYNCYTIAL VIRUS-VACCINE [J].
HALL, CB .
SCIENCE, 1994, 265 (5177) :1393-1394