Dibenzoacridinium derivatives: a new class of G-quadruplex ligands with anti-HIV-1 properties
TL;DR
The design, synthesis, and biophysical characterization of a novel class of G4-stabilizing ligands based on a positively charged dibenzoacridinium (DBA) core are reported, identifying DBAs as a new class of G-quadruplex ligands with anti-HIV properties.
Abstract
G-quadruplexes (G4s) are non-canonical nucleic acid structures formed by guanine-rich sequences that assemble into stacked guanine tetrads. These unusual RNA or DNA structures are implicated in essential regulatory processes in both human and viral genomes. In recent years, compounds that bind and stabilise G4s have emerged as promising antiviral agents against several viruses such as HIV-1, HCV or HPV. We report the design, synthesis, and biophysical characterization of a novel class of G4-stabilizing ligands based on a positively charged dibenzoacridinium (DBA) core. A combination of FRET-melting assays, fluorescence quenching assay (FQA), circular dichroism spectroscopy, native mass spectrometry, NMR titration, and molecular dynamics simulations confirmed that DBA ligands bind selectively to G4s, with thermal stabilization (ΔTm) values reaching +18 °C and dissociation constants (Kd) as low as 0.14 μM. In cellular assays, DBA4 and DBA5 compounds exhibited antiviral activity against HIV-1, with IC50 values of 1 μM and 3 μM, respectively. These results identify DBAs as a new class of G-quadruplex ligands with anti-HIV properties.