Flavonoids as noncompetitive inhibitors of Dengue virus NS2B-NS3 protease: Inhibition kinetics and docking studies

被引：127

作者：

Freitas de Sousa, Lorena Ramos ^{[1
,2
]}

Wu, Hongmei ^{[2
]}

Nebo, Liliane ^{[1
]}

Fernandes, Joao Batista ^{[1
]}

das Gracas Fernandes da Silva, Maria Fatima ^{[1
]}

Kiefer, Werner ^{[2
]}

Kanitz, Manuel ^{[3
]}

Bodem, Jochen ^{[4
]}

Diederich, Wibke E. ^{[3
]}

Schirmeister, Tanja ^{[2
]}

Vieira, Paulo Cezar ^{[1
]}

机构：

[1] Univ Fed Sao Carlos, Dept Quim, BR-13565905 Sao Paulo, Brazil

[2] Johannes Gutenberg Univ Mainz, Inst Pharm & Biochem, D-55128 Mainz, Germany

[3] Univ Marburg, Inst Pharmazeut Chem, D-35032 Marburg, Hessen, Germany

[4] Univ Wurzburg, Inst Virol & Immunbiol, D-97078 Wurzburg, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 03期

关键词：

Biflavone; Flavonol; Dengue virus; NS2B-NS3; protease; ANTIVIRAL ACTIVITY; TYPE-2; PROTEASE; NS3; PROTEIN; DERIVATIVES; HELICASE; DOMAIN;

D O I：

10.1016/j.bmc.2014.12.015

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

NS2B-NS3 is a serine protease of the Dengue virus considered a key target in the search for new antiviral drugs. In this study flavonoids were found to be inhibitors of NS2B-NS3 proteases of the Dengue virus serotypes 2 and 3 with IC50 values ranging from 15 to 44 mu M. Agathisflavone (1) and myricetin (4) turned out to be noncompetitive inhibitors of dengue virus serotype 2 NS2B-NS3 protease with K-i values of 11 and 4.7 mu M, respectively. Docking studies propose a binding mode of the flavonoids in a specific allosteric binding site of the enzyme. Analysis of biomolecular interactions of quercetin (5) with NT647-NHS-labeled Dengue virus serotype 3 NS2B-NS3 protease by microscale thermophoresis experiments, yielded a dissociation constant K-D of 20 mu M. Our results help to understand the mechanism of inhibition of the Dengue virus serine protease by flavonoids, which is essential for the development of improved inhibitors. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：466 / 470

页数：5

共 47 条

[1]

Potential anti-dengue medicinal plants: a review [J].

Abd Kadir, Siti Latifah ;

Yaakob, Harisun ;

Zulkifli, Razauden Mohamed .

JOURNAL OF NATURAL MEDICINES, 2013, 67 (04) :677-689

[2]

Broad Antiviral Activity of Carbohydrate-Binding Agents against the Four Serotypes of Dengue Virus in Monocyte-Derived Dendritic Cells [J].

Alen, Marijke M. F. ;

De Burghgraeve, Tine ;

Kaptein, Suzanne J. F. ;

Balzarini, Jan ;

Neyts, Johan ;

Schols, Dominique .

PLOS ONE, 2011, 6 (06)

[3]

Alkylated Flavanones from the Bark of Cryptocarya chartacea As Dengue Virus NS5 Polymerase Inhibitors [J].

Allard, Pierre-Marie ;

Dau, Elise Tran Huu ;

Eydoux, Cecilia ;

Guillemot, Jean-Claude ;

Dumontet, Vincent ;

Poullain, Cyril ;

Canard, Bruno ;

Gueritte, Francoise ;

Litaudon, Marc .

JOURNAL OF NATURAL PRODUCTS, 2011, 74 (11) :2446-2453

[4]

FLAVONOIDS AND OTHER BIOACTIVE PHENOLICS ISOLATED FROM Cenostigma macrophyllum (LEGUMINOSAE) [J].

Alves, Clayton Q. ;

David, Jorge M. ;

David, Juceni P. ;

Villareal, Cristiane F. ;

Soares, Milena B. P. ;

de Queiroz, Luciano P. ;

Aguiar, Rosane M. .

QUIMICA NOVA, 2012, 35 (06) :1137-1140

[5]

Best Practices in Dengue Surveillance: A Report from the Asia-Pacific and Americas Dengue Prevention Boards [J].

Beatty, Mark E. ;

Stone, Amy ;

Fitzsimons, David W. ;

Hanna, Jeffrey N. ;

Lam, Sai Kit ;

Vong, Sirenda ;

Guzman, Maria G. ;

Mendez-Galvan, Jorge F. ;

Halstead, Scott B. ;

Letson, G. William ;

Kuritsky, Joel ;

Mahoney, Richard ;

Margolis, Harold S. .

PLOS NEGLECTED TROPICAL DISEASES, 2010, 4 (11)

[6]

Functional characterization of the NS2B/NS3 protease complex from seven viruses belonging to different groups inside the genus Flavivirus [J].

Bessaud, Mael ;

Pastorino, Boris A. M. ;

Peyrefitte, Christophe N. ;

Rolland, Dorninique ;

Grandadam, Marc ;

Tolou, Hugues J. .

VIRUS RESEARCH, 2006, 120 (1-2) :79-90

[7]

BioSolveIT GmbH, 2014, LEADIT FLEXX VERS 2

[8]

Polar phenolic constituents from Schinus terebinthifolius Raddi (Anacardiaceae) [J].

Ceruks, Melina ;

Romoff, Paulete ;

Favero, Oriana A. ;

Lago, Joao Henrique G. .

QUIMICA NOVA, 2007, 30 (03) :597-599

[9]

The non-structural 3 (NS3) protein of dengue virus type 2 interacts with human nuclear receptor binding protein and is associated with alterations in membrane structure [J].

Chua, JJE ;

Ng, MML ;

Chow, VTK .

VIRUS RESEARCH, 2004, 102 (02) :151-163

[10]

Secundary metabolites from species of Anacardiaceae [J].

Correia, Suzimone de J. ;

David, Jueeni P. ;

David, Jorge M. .

QUIMICA NOVA, 2006, 29 (06) :1287-1300

← 1 2 3 4 5 →