Discovery, synthesis, and biological evaluation of a novel group of selective inhibitors of filoviral entry.
Discovery, synthesis, and biological evaluation of a novel group of selective inhibitors of filoviral entry.
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DOI：
10.1021/jm1008715
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发表时间：
2011-02-10
影响因子：
7.3
通讯作者：
Wardrop DJ
中科院分区：
文献类型：
--
作者：
Yermolina MV;Wang J;Caffrey M;Rong LL;Wardrop DJ
Herein, we report the development of an anti-filoviral screening system, based on a pseudotyping strategy, and its application in the discovery of a novel group of small molecules that selectively inhibit the Ebola and Marburg glycoprotein (GP)-mediated infection of human cells. Using Ebola Zaire GP-pseudotyped HIV particles bearing a luciferase reporter gene and 293T cells, a library of 237 small molecules was screened for inhibition of GP-mediated viral entry. From this assay, lead compound 8a was identified as a selective inhibitor of filoviral entry with an IC50 of 30 μM. In order to analyze functional group requirements for efficacy, a structure-activity relationship analysis of this 3,5-disubstituted isoxazole was then conducted with 56 isoxazole and triazole derivatives prepared using “click” chemistry. This study revealed that while the isoxazole ring can be replaced by a triazole system, the 5-(diethylamino)acetamido substituent found in 8a is required for inhibition of viral-cell entry. Variation of the 3-aryl substituent provided a number of more potent anti-viral agents with IC50 values ranging to 2.5 μM. Lead compound 8a and three of its derivatives were also found to block the Marburg glycoprotein (GP)-mediated infection of human cells.
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影响因子：
15
作者：
Himo, F;Lovell, T;Fokin, VV
通讯作者：
Fokin, VV
影响因子：
3.6
作者：
Cleij, MC;Scrimin, P;Tonellato, U
通讯作者：
Tonellato, U
DOI：
10.1038/nrd1694
发表时间：
2005-04
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Burnett JC;Henchal EA;Schmaljohn AL;Bavari S
通讯作者：
Bavari S
影响因子：
56.9
作者：
Leroy, EM;Rouquet, P;Rollin, PE
通讯作者：
Rollin, PE
影响因子：
5.4
作者：
HE, JL;CHOE, S;LANDAU, NR
通讯作者：
LANDAU, NR