期刊
NUCLEIC ACID THERAPEUTICS
卷 31, 期 1, 页码 68-81出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/nat.2020.0869
关键词
human papillomavirus; G-quadruplex; antiviral; ligands; organotypic rafts
资金
- FCT -Foundation for Science and Technology [SFRH/BD/122953/2016]
- project Acoes Integradas Luso-Francesas'' [TC-15/17]
- Cooperacao Cientifica e Tecnologica FCT/Acordo Pessoa [5079]
- FCT - Fundo Social Europeu and Programa Operacional Potencial Humano [IF/00959/2015]
- MIT Portugal project BIODEVICE [MIT-EXPL/BIO/0008/2017]
- UTAustin FCT project DREAM [UTAP-EXPL/NTec/0015/2017]
- FCT/MCT [UIDB/00709/2020, ROTEIRO/0031/2013-PINFRA/22161/2016]
- FEDER through COMPETE 2020
- POCI
- PORL
- PIDDAC
- SYMBIT project from the ERDF [CZ.02.1.01/0.0/0.0/15_003/0000477]
- [UTAP-EXPL/NTec/0015/2017-B1]
- Fundação para a Ciência e a Tecnologia [UTAP-EXPL/NTec/0015/2017] Funding Source: FCT
This study reports the screening of ligands for their binding and stabilizing ability with G-quadruplexes (G4) found in human Papillomavirus (HPV) genomes. The results show that HPV G-quadruplexes exhibit structural polymorphism upon ligand binding, impacting transcription, replication, and viral protein production. Targeting HPV G4s may offer an alternative route for the development of novel antiviral therapies, as demonstrated by the significant antiviral effect of the acridine derivative C-8 in HPV18-infected organotypic raft cultures.
Herein, we report, for the first time, the screening of several ligands in terms of their ability to bind and stabilize G-quadruplexes (G4) found in seven human Papillomavirus (HPV) genomes. Using a variety of biophysical assays, HPV G-quadruplexes were shown to possess a high degree of structural polymorphism upon ligand binding, which may have an impact on transcription, replication, and viral protein production. A sequence found in high-risk HPV16 genotype folds into multiple non-canonical DNA structures; it was converted into a major G4 conformation upon interaction with a well-characterized highly selective G4 ligand, PhenDC3, which may have an impact on the viral infection. Likewise, HPV57 and 58, which fold into multiple G4 structures, were found to form single stable complexes in the presence of two other G4 ligands, C-8 and pyridostatin, respectively. In addition, one of the selected compounds, the acridine derivative C-8, demonstrated a significant antiviral effect in HPV18-infected organotypic raft cultures. Altogether, these results indicate that targeting HPV G4s may be an alternative route for the development of novel antiviral therapies.
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