title: Library-based discovery and characterization of daphnane diterpenes as potent and selective HIV inhibitors in Daphne gnidium.
abstract: Despite the existence of an extended armamentarium of effective synthetic drugs to treat HIV, there is a continuing need for new potent and affordable drugs. Given the successful history of natural product based drug discovery, a library of close to one thousand plant and fungal extracts was screened for antiretroviral activity. A dichloromethane extract of the aerial parts of Daphne gnidium exhibited strong antiretroviral activity and absence of cytotoxicity. With the aid of HPLC-based activity profiling, the antiviral activity could be tracked to four daphnane derivatives, namely, daphnetoxin (1), gnidicin (2), gniditrin (3), and excoecariatoxin (4). Detailed anti-HIV profiling revealed that the pure compounds were active against multidrug-resistant viruses irrespective of their cellular tropism. Mode of action studies that narrowed the site of activity to viral entry events suggested a direct interference with the expression of the two main HIV co-receptors, CCR5 and CXCR4, at the cell surface by daphnetoxin (1).
authors.affiliation: InPheno AG, Basel, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Vidal
authors.forename: Olivier
authors.initials: O
authors.lastname: Potterat
authors.forename: Séverine
authors.initials: S
authors.lastname: Louvel
authors.forename: François
authors.initials: F
authors.lastname: Hamy
authors.forename: Mahdi
authors.initials: M
authors.lastname: Mojarrab
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Sanglier
authors.forename: Thomas
authors.initials: T
authors.lastname: Klimkait
authors.forename: Matthias
authors.initials: M
authors.lastname: Hamburger
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D032364:Daphne / Q000737:chemistry*; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D019083:Mediterranean Region; D015394:Molecular Structure; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D004224:Diterpenes; D006576:Heterocyclic Compounds, 4 or More Rings; D019718:Receptors, CXCR4; C452759:daphnetoxin; C010461:gniditrin; C010459:gnidicin