Synthesis, Binding and Antiviral Properties of Potent Core-Extended Naphthalene Diimides Targeting the HIV‑1 Long Terminal Repeat Promoter G‑Quadruplexes

We have previously reported that
stabilization of the G-quadruplex
structures in the HIV-1 long terminal repeat (LTR) promoter suppresses
viral transcription. Here we sought to develop new G-quadruplex ligands
to be exploited as antiviral compounds by enhancing binding toward
the viral G-quadruplex structures. We synthesized naphthalene diimide
derivatives with a lateral expansion of the aromatic core. The new
compounds were able to bind/stabilize the G-quadruplex to a high extent,
and some of them displayed clear-cut selectivity toward the viral
G-quadruplexes with respect to the human telomeric G-quadruplexes.
This feature translated into low nanomolar anti-HIV-1 activity toward
two viral strains and encouraging selectivity indexes. The selectivity
depended on specific recognition of LTR loop residues; the mechanism
of action was ascribed to inhibition of LTR promoter activity in cells.
This is the first example of G-quadruplex ligands that show increased
selectivity toward the viral G-quadruplexes and display remarkable
antiviral activity.