A cellular screening platform, stably expressing DENV2 NS5, defines a novel anti-DENV mechanism of action of Apigenin based on STAT2 activation

被引：11

作者：

Acchioni, Chiara ^{[1
]}

Acchioni, Marta ^{[1
]}

Mancini, Flavia ^{[2
]}

Amendola, Antonello ^{[1
]}

Marsili, Giulia ^{[1
]}

Tirelli, Valentina ^{[4
]}

Gwee, Chin Piaw ^{[5
]}

Chan, Kitti Wing-Ki ^{[5
]}

Sandini, Silvia ^{[1
]}

Bisbocci, Monica ^{[3
]}

Mysara, Mohamed ^{[6
]}

ElHefnawi, Mahmoud ^{[7
]}

Sanchez, Massimo ^{[4
]}

Venturi, Giulietta ^{[1
]}

Barreca, Maria Letizia ^{[8
]}

Manfroni, Giuseppe ^{[8
]}

Bresciani, Alberto ^{[3
,10
]}

Vasudevan, Subhash G. ^{[5
]}

Sgarbanti, Marco ^{[1
,9
]}

机构：

[1] Ist Super Sanita, Dept Infect Dis, Viale Regina Elena 299, I-00161 Rome, Italy

[2] Ist Super Sanita, Natl HIV AIDS Res Ctr, Viale Regina Elena 299, I-00161 Rome, Italy

[3] IRBM SpA, Dept Translat & Discovery Res, Rome, Italy

[4] Ist Super Sanita, Core Facil Serv, Viale Regina Elena 299, I-00161 Rome, Italy

[5] Duke NUS Med Sch, Program Emerging Infect Dis, 8 Coll Rd, Singapore 169857, Singapore

[6] Nile Univ, Ctr Informat Sci CIS, Sch Informat Technol & Comp Sci ITCS, Bioinformat Grp, Giza, Egypt

[7] Natl Res Ctr, Informat & Syst Dept, Biomed Informat & Chemoinformat Grp, Cairo, Egypt

[8] Univ Perugia, Dept Pharmaceut Sci, Via Liceo 1, I-06123 Perugia, Italy

[9] Ist Super Sanita, Dept Infect Dis DMI, Viale Regina Elena 299, I-00161 Rome, Italy

[10] Exscientia ltd, Schrodinger Bldg,Heatley Rd,Oxford Sci Pk, Oxford, England

来源：

VIROLOGY | 2023年 / 583卷

关键词：

Dengue virus; NS5; STAT2; Apigenin; Luteolin; Cell-based assays; INTERFERENCE COMPOUNDS PAINS; DENGUE VIRUS-INFECTION; MEGAKARYOCYTIC DIFFERENTIATION; ALPHA-INTERFERON; CELLS; INHIBITION; POLYMERASE; PROTEIN; LEUKEMIA; RNA;

D O I：

10.1016/j.virol.2023.03.016

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Type I interferon (IFN-I) evasion by Dengue virus (DENV) is key in DENV pathogenesis. The non-structural protein 5 (NS5) antagonizes IFN-I response through the degradation of the signal transducer and activator of transcription 2 (STAT2). We developed a K562 cell-based platform, for high throughput screening of compounds potentially counteracting the NS5-mediated antagonism of IFN-I signaling. Upon a screening with a library of 1220 approved drugs, 3 compounds previously linked to DENV inhibition (Apigenin, Chrysin, and Luteolin) were identified. Luteolin and Apigenin determined a significant inhibition of DENV2 replication in Huh7 cells and the restoration of STAT2 phosphorylation in both cell systems. Apigenin and Luteolin were able to stimulate STAT2 even in the absence of infection. Despite the "promiscuous" and "pan-assay-interfering" nature of Luteolin, Apigenin promotes STAT2 Tyr 689 phosphorylation and activation, highlighting the importance of screening for compounds able to interact with host factors, to counteract viral proteins capable of dampening innate immune responses.

引用

页码：1 / 13

页数：13

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