Denbinobin, a naturally occurring 1,4-phenanthrenequinone, inhibits HIV-1 replication through an NF-kappaB-dependent pathway.
Anthraquinones and structurally related compounds have been recently shown to exert antiviral activities and thus exhibit a therapeutic potential. In this study we report the isolation of the 1,4-phenanthrenequinone, denbinobin, from a variety of Cannabis sativa. Denbinobin does not affect the reverse transcription and integration steps of the viral cycle but prevents HIV-1 reactivation in Jurkat T cells activated by TNFalpha, mAbs anti-CD3/CD28 or PMA. In addition, denbinobin inhibits HIV-1-LTR activity at the level of transcription elongation and also TNFalpha-induced HIV-1-LTR transcriptional activity. We found that denbinobin prevents the binding of NF-kappaB to DNA and the phosphorylation and degradation of NF-kappaB inhibitory protein, IkappaBalpha, and inhibits the phosphorylation of the NF-kappaB p65 subunit in TNFalpha-stimulated cells. These results highlight the potential of the NF-kappaB transcription factor as a target for natural anti-HIV-1 compounds such as 1,4-phenanthrenequinones, which could serve as lead compounds for the development of an alternative therapeutic approach against AIDS.
Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Facultad de Medicina, Córdoba, Spain.
Gonzalo
G
Sánchez-Duffhues
Marco A
MA
Calzado
Amaya García
AG
de Vinuesa
Francisco J
FJ
Caballero
Abdellah
A
Ech-Chahad
Giovanni
G
Appendino
Karsten
K
Krohn
Bernd L
BL
Fiebich
Eduardo
E
Muñoz
D000880:Anthraquinones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010616:Phenanthrenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects* / Q000502:physiology
D000880:Anthraquinones; D016328:NF-kappa B; D010616:Phenanthrenes; D010936:Plant Extracts; C436544:denbinobin; C105959:1,4-phenanthrenequinone