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

Abstract

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.

Template‐Mediated Stabilization of a DNA G‐Quadruplex formed in the HIV‐1 Promoter and Comparative Binding Studies

“…Indeed, the G4‐forming sequences appear to be highly conserved among subspecies thereby suggesting functional significance. For instance, independent studies have shown that derivatives of porphyrin, acridine, or naphthalene could interact with HIV‐G4 structures leading to the inhibition of key steps in the HIV‐1 viral cell cycle.…”

Visualization of DNA G-quadruplexes in herpes simplex virus 1-infected cells

“…Because of the inherent different mechanism of action, G4 ligands could be envisaged as therapeutic options against HSV-1 strains resistant to current anti-herpetic drugs. In this direction, we have recently shown the availability of small molecules that target the HIV-1 G4s with a degree of selectivity vs the cellular telomeric G4s, resulting in very good antiviral properties (67). These data indicate the possibility to identify ligands selective for HSV-1 G4s.…”

The cellular protein hnRNP A2/B1 enhances HIV-1 transcription by unfolding LTR promoter G-quadruplexes

“…We and other groups have identified functionally significant G4s in the Nef coding region16 and in the unique long terminal repeat (LTR) promoter171819 of HIV-1. When the HIV-1 G4s were stabilized by G4 ligands, antiviral effects, mainly dependent on inhibition of LTR-mediated transcription, were observed182021. Furthermore, the cellular protein nucleolin has been shown to stabilize the HIV-1 LTR G4s and induce potent inhibition of viral transcription22.…”