1. Academic Validation
  2. Naphthalene Diimide-Tetraazacycloalkane Conjugates Are G-Quadruplex-Based HIV-1 Inhibitors with a Dual Mode of Action

Naphthalene Diimide-Tetraazacycloalkane Conjugates Are G-Quadruplex-Based HIV-1 Inhibitors with a Dual Mode of Action

  • ACS Infect Dis. 2024 Jan 4. doi: 10.1021/acsinfecdis.3c00453.
Matteo Nadai 1 Filippo Doria 2 Ilaria Frasson 1 Rosalba Perrone 3 Valentina Pirota 2 Greta Bergamaschi 4 Mauro Freccero 2 Sara N Richter 1 5
Affiliations

Affiliations

  • 1 Department of Molecular Medicine, University of Padua, Via Gabelli 63, 35121 Padua, Italy.
  • 2 Department of Chemistry, University of Pavia, V.le Taramelli 10, 27100 Pavia, Italy.
  • 3 Buck Institute for Research on Aging, Novato, California 94945, United States.
  • 4 National Research Council of Italy, Istituto di Scienze e Tecnologie Chimiche "Giulio Natta" (SCITEC-CNR), Via Mario Bianco 9, 20131 Milano, Italy.
  • 5 Microbiology and Virology Unit, Padua University Hospital, 35121 Padua, Italy.
Abstract

Human immunodeficiency virus 1 (HIV-1) therapeutic regimens consist of three or more drugs targeting different steps of the viral life cycle to limit the emergence of viral resistance. In line with the multitargeting strategy, here we conjugated a naphthalene diimide (NDI) moiety with a tetraazacycloalkane to obtain novel naphthalene diimide (NDI)-tetraazacycloalkane conjugates. The NDI inhibits the HIV-1 promoter activity by binding to LTR G-quadruplexes, and the tetraazacycloalkane mimics AMD3100, which blocks HIV entry into cells by interfering with the CXCR4 coreceptor. We synthesized, purified, and tested the metal-free NDI-tetraazacycloalkane conjugate and the two derived metal-organic complexes (MOCs) that incorporate Cu2+ and Zn2+. The NDI-MOCs showed enhanced binding to LTR G4s as assessed by FRET and CD assays in vitro. They also showed enhanced activity in cells where they dose-dependently reduced LTR promoter activity and inhibited viral entry only of the HIV-1 strain that exploited the CXCR4 coreceptor. The time of addition assay confirmed the dual targeting at the different HIV-1 steps. Our results indicate that the NDI-MOC conjugates can simultaneously inhibit viral entry, by targeting the CXCR4 coreceptor, and LTR promoter activity, by stabilizing the LTR G-quadruplexes. The approach of combining multiple targets in a single compound may streamline treatment regimens and improve the overall patient outcomes.

Keywords

G-quadruplex; HIV; LTR; metal–organic complexes; naphthalene diimides.

Figures
Products