Dibenzoacridinium Derivatives as a New Class of G-Quadruplex Ligands with Antiviral Properties

Abstract

G-quadruplexes (G4s) are nucleic acid structures formed by guanine-rich sequences that are based on the formation of guanine tetrads. These unusual RNA or DNA structures are implicated in key biological processes in human cells as well as in microbes. In recent years, compounds that bind and stabilise G4s have emerged as promising antiviral molecules against several viruses such as HIV-1, HCV or HPV. Here, we have synthesised a new class of G4 stabilising ligands that are based on a positively charged Dibenzoacridinium (DBA) core. Using the FRET-melting assay, the FQA assay, Circular dichroism and native mass spectrometry we show that DBA ligands bind specifically to G4 structures in vitro. We also demonstrate that DBAs are capable of inhibiting native HIV-1 infectivity with an IC50 ranging from 0.9 to 4 µM. Thus, DBAs represent a new class of antiviral drugs that targets viral RNAs, the actual source of the disease.

Keywords: HIV-1, G-Quadruplex, dibenzoacridinium, G4 ligands, G4 binders, antiviral molecules