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.

ARNA Laboratory Université de Bordeaux Inserm U1212 CNRS UMR 5320 IECB Pessac France

Centro de Ciências e Tecnologias Nucleares Instituto Superior Técnico Universidade de Lisboa Bobadela LRS Portugal

CICS UBI Centro de Investigação em Ciências da Saúde Universidade da Beira Interior Covilhã Portugal

Department Microbiology and Immunology Penn State College of Medicine Hershey Pennsylvania USA

Institute of Biophysics of the CAS v v i Brno Czech Republic

Laboratoire d'Optique et Biosciences Ecole Polytechnique CNRS INSERM Institut Polytechnique de Paris Palaiseau France

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