title: 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.
authors.affiliation: Department of Molecular Medicine, University of Padua , via Gabelli 63, 35121 Padua, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Perrone
authors.affiliation: Department of Chemistry, University of Pavia , V.le Taramelli 10, 27100 Pavia, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Doria
authors.affiliation: Department of Molecular Medicine, University of Padua , via Gabelli 63, 35121 Padua, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Butovskaya
authors.affiliation: Department of Molecular Medicine, University of Padua , via Gabelli 63, 35121 Padua, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Frasson
authors.affiliation: Department of Chemistry, University of Pavia , V.le Taramelli 10, 27100 Pavia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Botti
authors.affiliation: Department of Molecular Medicine, University of Padua , via Gabelli 63, 35121 Padua, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Scalabrin
authors.affiliation: Department of Molecular Medicine, University of Padua , via Gabelli 63, 35121 Padua, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Lago
authors.affiliation: Department of Chemistry, University of Pavia , V.le Taramelli 10, 27100 Pavia, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Grande
authors.affiliation: Department of Molecular Medicine, University of Padua , via Gabelli 63, 35121 Padua, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Nadai
authors.affiliation: Department of Chemistry, University of Pavia , V.le Taramelli 10, 27100 Pavia, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Freccero
authors.affiliation: Department of Molecular Medicine, University of Padua , via Gabelli 63, 35121 Padua, Italy.
authors.forename: Sara N
authors.initials: SN
authors.lastname: Richter
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054856:G-Quadruplexes; D057809:HEK293 Cells; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007094:Imides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D007094:Imides; D008024:Ligands; D009281:Naphthalenes