2015 | OriginalPaper | Buchkapitel
G-Quadruplexes in the Human Immunodeficiency Virus-1 and Herpes Simplex Virus-1: New Targets for Antiviral Activity by Small Molecules
verfasst von : Rosalba Perrone, Sara Artusi, Elena Butovskaya, Matteo Nadai, Christophe Pannecouque, Sara N. Richter
Erschienen in: 5th International Conference on Biomedical Engineering in Vietnam
Aktivieren Sie unsere intelligente Suche, um passende Fachinhalte oder Patente zu finden.
Wählen Sie Textabschnitte aus um mit Künstlicher Intelligenz passenden Patente zu finden. powered by
Markieren Sie Textabschnitte, um KI-gestützt weitere passende Inhalte zu finden. powered by
G-quadruplexes (G-4s) are G-rich non-canonical four-stranded conformations of nucleic acids that act as structural switches of cellular processes. Very little is known on the role of G-4s in viruses yet. The human immunodeficiency virus-1 (HIV-1) and the human herpes simplex virus-1 (HSV-1) are important human pathogens: HIV-1 is the etiological agent for the acquired immune deficiency syndrome (AIDS), while HSV-1 causes vesicular lesions on the mucous membranes, but it can also cause serious diseases, such as encephalitis, in immunocompromised patients and it increases sexual transmission of HIV-1. Both viruses permanently install into the human host and no cure to eradicate them has yet been developed.
We have shown that DNA G-4s arise in the integrated DNA genome, in the long terminal repeat (LTR) promoter, and inhibit viral transcription. We now show that the LTR sequence is present also in the HIV-1 RNA genome where it can fold into very stable parallel-like G-4 structures. Both DNA and RNA G-4s were stabilized by a G-4 ligand, BRACO-19, which exerted antiviral activity against a broad range of virus strains, host cells and types of infections. BRACO-19 was active both at the reverse transcription step and during post-integration events, which are compatible with BRACO-19 activity on G-4 structures.
Also HSV-1, which is characterized by a genome remarkably rich in guanines, presents clusters of repeated sequences forming very stable G-4s in key regions of the HSV-1 genome. Treatment of HSV-1 infected cells with BRACO-19 induced significant inhibition of virus production, general reduction of viral transcripts and of intracellular viral DNA. BRACO-19 was able to inhibit Taq polymerase processing at G-4 sites.
This work, besides presenting the first evidence of extended G-4 sites in key regions of the HIV-1 and HSV-1 genomes, opens up new potential antiviral therapeutic interventions based on the use of G-4 ligands.