Open AccessSynthesis, Binding and Antiviral Properties of Potent Core-Extended Naphthalene Diimides Targeting the HIV-1 Long Terminal Repeat Promoter G-Quadruplexes
Author(s) -
Rosalba Perrone,
Filippo Doria,
Elena Butovskaya,
Ilaria Frasson,
Silvia Botti,
Matteo Scalabrin,
Sara Lago,
Vincenzo Grande,
Matteo Nadai,
Mauro Freccero,
Sara N. Richter
Publication year - 2015
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.5b01283
Subject(s) - chemistry , g quadruplex , selectivity , long terminal repeat , transcription (linguistics) , structure–activity relationship , stereochemistry , microbiology and biotechnology , biochemistry , dna , gene , biology , gene expression , in vitro , linguistics , philosophy , catalysis
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.