A pan-serotype dengue virus inhibitor targeting the NS3-NS4B interaction

被引：126

作者：

Kaptein, Suzanne J. F. ^{[1
]}

Goethals, Olivia ^{[2
]}

Kiemel, Dominik ^{[3
]}

Marchand, Arnaud ^{[4
]}

Kesteleyn, Bart ^{[5
]}

Bonfanti, Jean-Francois ^{[6
,11
]}

Bardiot, Dorothee ^{[4
]}

Stoops, Bart ^{[5
]}

Jonckers, Tim H. M. ^{[5
]}

Dallmeier, Kai ^{[1
]}

Geluykens, Peggy ^{[5
,12
]}

Thys, Kim ^{[5
]}

Crabbe, Marjolein ^{[5
]}

Chatel-Chaix, Laurent ^{[3
,13
]}

Muenster, Max ^{[3
]}

Querat, Gilles ^{[7
]}

Touret, Franck ^{[7
]}

de Lamballerie, Xavier ^{[7
]}

Raboisson, Pierre ^{[5
,14
]}

Simmen, Kenny ^{[5
]}

Chaltin, Patrick ^{[4
,8
]}

Bartenschlager, Ralf ^{[3
,9
]}

Van Loock, Marnix ^{[2
]}

Neyts, Johan ^{[1
,10
]}

机构：

[1] Katholieke Univ Leuven, Rega Inst Med Res, Dept Microbiol Immunol & Transplantat, Lab Virol & Chemotherapy, Leuven, Belgium

[2] Janssen Pharmaceut, Janssen Global Publ Hlth, Beerse, Belgium

[3] Heidelberg Univ, Mol Virol, Dept Infect Dis, Heidelberg, Germany

[4] Cistim Leuven, Leuven, Belgium

[5] Janssen Pharmaceut, Janssen Res & Dev, Beerse, Belgium

[6] Janssen Cilag, Janssen Infect Dis Discovery, Val De Reuil, France

[7] Aix Marseille Univ, Inserm 1207, Unite Virus Emergents UVE, IRD 190,IHU Mediterranee Infect, Marseille, France

[8] Katholieke Univ Leuven, Ctr Drug Design & Discovery CD3, Leuven, Belgium

[9] German Ctr Infect Res, Heidelberg Partner Site, Heidelberg, Germany

[10] Global Virus Network GVN, Baltimore, MD USA

[11] Galapagos, Romainville, France

[12] Charles River Beerse, Discovery, Beerse, Belgium

[13] Ctr Armand Frappier Sante Biotechnol, Inst Natl Rech Sci, Quebec City, PQ, Canada

[14] Aligos, Leuven, Belgium

来源：

NATURE | 2021年 / 598卷 / 7881期

基金：

英国惠康基金;

关键词：

NS4B; REPLICATION; NS3;

D O I：

10.1038/s41586-021-03990-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The small molecule JNJ-A07 interferes with the interaction between the NS3 and NS4B proteins of dengue virus and reduces the viral load in mice even when first administered at peak viraemia. Dengue virus causes approximately 96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue(1,2). There are no antiviral agents available to prevent or treat dengue. Here, we describe a highly potent dengue virus inhibitor (JNJ-A07) that exerts nanomolar to picomolar activity against a panel of 21 clinical isolates that represent the natural genetic diversity of known genotypes and serotypes. The molecule has a high barrier to resistance and prevents the formation of the viral replication complex by blocking the interaction between two viral proteins (NS3 and NS4B), thus revealing a previously undescribed mechanism of antiviral action. JNJ-A07 has a favourable pharmacokinetic profile that results in outstanding efficacy against dengue virus infection in mouse infection models. Delaying start of treatment until peak viraemia results in a rapid and significant reduction in viral load. An analogue is currently in further development.

引用

页码：504 / +

页数：26

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