In silico identification, design and synthesis of novel piperazine-based antiviral agents targeting the hepatitis C virus helicase

被引：18

作者：

Bassetto, Marcella ^{[1
]}

Leyssen, Pieter ^{[2
]}

Neyts, Johan ^{[2
]}

Yerukhimovich, Mark M. ^{[3
]}

Frick, David N. ^{[3
]}

Courtney-Smith, Matthew ^{[1
]}

Brancale, Andrea ^{[1
]}

机构：

[1] Cardiff Sch Pharm & Pharmaceut Sci, King Edward VII Ave, Cardiff CF10 3NB, Wales

[2] Univ Leuven, Rega Inst Med Res, Leuven, Belgium

[3] Univ Wisconsin Milwaukee, Dept Chem & Biochem, Milwaukee, WI 53211 USA

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 125卷

关键词：

Structure-based virtual screening; HCV NS3-helicase; Piperazine derivatives; Anti-HCV activity; NS3 helicase inhibitors; HCV NS5A INHIBITORS; NS3 RNA HELICASE; PRIMULINE DERIVATIVES; NUCLEIC-ACID; RESISTANCE; TRANSLOCATION; ATP; HYDROLYSIS; BINDING;

D O I：

10.1016/j.ejmech.2016.10.043

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A structure-based virtual screening of commercial compounds was carried out on the HCV NS3 helicase structure, with the aim to identify novel inhibitors of HCV replication. Among a selection of 13 commercial structures, one compound was found to inhibit the subgenomic HCV replicon in the low micromolar range. Different series of new piperazine-based analogues were designed and synthesised, and among them, several novel structures exhibited antiviral activity in the HCV replicon assay. Some of the new compounds were also found to inhibit HCV NS3 helicase function in vitro, and one directly bound NS3 with a dissociation constant of 570 +/- 270 nM. (C) 2016 Elsevier Masson SAS. All rights reserved.

引用

页码：1115 / 1131

页数：17

共 35 条

[1] Visualizing ATP-Dependent RNA Translocation by the NS3 Helicase from HCV [J].

Appleby, Todd C. ;

Anderson, Robert ;

Fedorova, Olga ;

Pyle, Anna M. ;

Wang, Ruth ;

Liu, Xiaohong ;

Brendza, Katherine M. ;

Somoza, John R. .

JOURNAL OF MOLECULAR BIOLOGY, 2011, 405 (05) :1139-1153

[2] Hepatitis C virus replicons: potential role for drug development [J].

Bartenschlager, R .

NATURE REVIEWS DRUG DISCOVERY, 2002, 1 (11) :911-916

[3] Microwave-assisted synthesis and characterization of novel metal-free and metallophthalocyanines containing four 14-membered tetraaza macrocycles [J].

Biyiklioglu, Zekeriya ;

Kantekin, Halit ;

Oezil, Musa .

JOURNAL OF ORGANOMETALLIC CHEMISTRY, 2007, 692 (12) :2436-2440

[4]

Carvalho J F, 1991, RD Patent, Patent No. [9110645A2, 9110645]

[5]

Food and Drug Administration, 2013, FDA APPR NEW TREATM

[6] Antiviral activity and resistance of HCV NS5A replication complex inhibitors [J].

Gao, Min .

CURRENT OPINION IN VIROLOGY, 2013, 3 (05) :514-520

[7]

Gritsenko Diana, 2015, P T, V40, P256

[8] Three conformational snapshots of the hepatitis C virus NS3 helicase reveal a ratchet translocation mechanism [J].

Gu, Meigang ;

Rice, Charles M. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (02) :521-528

[9] Cost Analysis of Sofosbuvir/Ribavirin Versus Sofosbuvir/Simeprevir for Genotype 1 Hepatitis C Virus in Interferon-Ineligible/Intolerant Individuals [J].

Hagan, Liesl M. ;

Sulkowski, Mark S. ;

Schinazi, Raymond F. .

HEPATOLOGY, 2014, 60 (01) :37-45

[10] IDENTIFICATION AND ANALYSIS OF INHIBITORS TARGETING THE HEPATITIS C VIRUS NS3 HELICASE [J].

Hanson, Alicia M. ;

Hernandez, John J. ;

Shadrick, William R. ;

Frick, David N. .

RNA HELICASES, 2012, 511 :463-483

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