TY - JOUR
T1 - Human Papillomavirus G-Rich Regions as Potential Antiviral Drug Targets
AU - Carvalho, Josué
AU - Lopes-Nunes, Jéssica
AU - Campello, Maria Paula Cabral
AU - Paulo, António
AU - Milici, Janice
AU - Meyers, Craig
AU - Mergny, Jean Louis
AU - Salgado, Gilmar F.
AU - Queiroz, João A.
AU - Cruz, Carla
N1 - Funding Information:
J. Carvalho acknowledges a doctoral fellowship grant from the FCT – Foundation for Science and Technology ref. SFRH/BD/122953/2016. Jéssica Lopes-Nunes acknowledges the fellowship reference UTAP-EXPL/NTec/0015/2017-B1. This work was supported by project “Ações Integradas Luso-Francesas” ref. TC-15/17, “Cooperação Cientifica e Tecnológica FCT/Acordo Pessoa” project ref. 5079, FCT project ref. IF/00959/2015 financed by Fundo Social Europeu and Programa Operacional Potencial Humano, MIT Portugal project BIODEVICE ref. MIT-EXPL/BIO/0008/2017, and UTAustin FCT project DREAM ref. UTAP-EXPL/NTec/0015/2017. The authors thank FCT/MCT for the financial support to CICS-UBI UIDB/00709/2020 research unit and to the Portuguese NMR Network (ROTEIRO/0031/2013-PINFRA/22161/2016), through national funds and, where applicable, co-financed by the FEDER through COMPETE 2020, POCI, PORL, and PIDDAC. This work was also supported by the SYMBIT project reg. no. CZ.02.1.01/0.0/0.0/15_003/0000477 financed from the ERDF.
Publisher Copyright:
© Copyright 2021, Mary Ann Liebert, Inc., publishers.
PY - 2021/2
Y1 - 2021/2
N2 - 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, C8 and pyridostatin, respectively. In addition, one of the selected compounds, the acridine derivative C8, 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.
AB - 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, C8 and pyridostatin, respectively. In addition, one of the selected compounds, the acridine derivative C8, 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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U2 - 10.1089/nat.2020.0869
DO - 10.1089/nat.2020.0869
M3 - Article
C2 - 33121376
AN - SCOPUS:85100988111
VL - 31
SP - 68
EP - 81
JO - Oligonucleotides
JF - Oligonucleotides
SN - 2159-3337
IS - 1
ER -