Identification of a Small-Molecule Entry Inhibitor for Filoviruses

被引：86

作者：

Basu, Arnab ^{[1
]}

Li, Bing ^{[1
]}

Mills, Debra M. ^{[1
]}

Panchal, Rekha G. ^{[2
]}

Cardinale, Steven C. ^{[1
]}

Butler, Michelle M. ^{[1
]}

Peet, Norton P. ^{[1
]}

Majgier-Baranowska, Helena ^{[1
]}

Williams, John D. ^{[1
]}

Patel, Ishan ^{[1
]}

Moir, Donald T. ^{[1
]}

Bavari, Sina ^{[2
]}

Ray, Ranjit ^{[3
]}

Farzan, Michael R. ^{[4
]}

Rong, Lijun ^{[5
]}

Bowlin, Terry L. ^{[1
]}

机构：

[1] Microbiotix Inc, Worcester, MA 01605 USA

[2] USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA

[3] St Louis Univ, Dept Internal Med, St Louis, MO 63110 USA

[4] Harvard Univ, Sch Med, Dept Mol Biol & Genet, Southborough, MA 01772 USA

[5] Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA

来源：

JOURNAL OF VIROLOGY | 2011年 / 85卷 / 07期

基金：

美国国家卫生研究院;

关键词：

EBOLA-VIRUS GLYCOPROTEIN; ACUTE RESPIRATORY SYNDROME; FOLATE RECEPTOR-ALPHA; MEASLES-VIRUS; TARGET SITE; IN-VITRO; DC-SIGN; INFECTION; MARBURG; DETERMINANTS;

D O I：

10.1128/JVI.01456-10

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Ebola virus (EBOV) causes severe hemorrhagic fever, for which therapeutic options are not available. Preventing the entry of EBOV into host cells is an attractive antiviral strategy, which has been validated for HIV by the FDA approval of the anti-HIV drug enfuvirtide. To identify inhibitors of EBOV entry, the EBOV envelope glycoprotein (EBOV-GP) gene was used to generate pseudotype viruses for screening of chemical libraries. A benzodiazepine derivative (compound 7) was identified from a high-throughput screen (HTS) of small-molecule compound libraries utilizing the pseudotype virus. Compound 7 was validated as an inhibitor of infectious EBOV and Marburg virus (MARV) in cell-based assays, with 50% inhibitory concentrations (IC(50)s) of 10 mu M and 12 mu M, respectively. Time-of-addition and binding studies suggested that compound 7 binds to EBOV-GP at an early stage during EBOV infection. Preliminary Schrodinger SiteMap calculations, using a published EBOV-GP crystal structure in its prefusion conformation, suggested a hydrophobic pocket at or near the GP1 and GP2 interface as a suitable site for compound 7 binding. This prediction was supported by mutational analysis implying that residues Asn69, Leu70, Leu184, Ile185, Leu186, Lys190, and Lys191 are critical for the binding of compound 7 and its analogs with EBOV-GP. We hypothesize that compound 7 binds to this hydrophobic pocket and as a consequence inhibits EBOV infection of cells, but the details of the mechanism remain to be determined. In summary, we have identified a novel series of benzodiazepine compounds that are suitable for optimization as potential inhibitors of filoviral infection.

引用

页码：3106 / 3119

页数：14

共 64 条

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