title: Jatrophane diterpenes as inhibitors of chikungunya virus replication: structure-activity relationship and discovery of a potent lead.
abstract: Bioassay-guided purification of an EtOAc extract of the whole plant of Euphorbia amygdaloides ssp. semiperfoliata using a chikungunya virus-cell-based assay led to the isolation of six new (1-4, 9, and 10) and six known (5-7, 8, 11, and 12) jatrophane esters. Their planar structures and relative configurations were determined by extensive spectroscopic analysis, and their absolute configurations by X-ray analysis. These compounds were investigated for selective antiviral activity against chikungunya virus (CHIKV), Semliki Forest virus, Sindbis virus, and HIV-1 and HIV-2 viruses. Compound 3 was found to be the most potent and selective inhibitor of the replication of CHIKV and of HIV-1 and HIV-2 (EC50 = 0.76, IC50 = 0.34 and 0.043 μM, respectively). A preliminary structure-activity relationship study demonstrated that potency and selectivity are very sensitive to the substitution pattern on the jatrophane skeleton. Although replication strategies of CHIK and HIV viruses are quite different, the mechanism of action by which these compounds act may involve a similar target for both viruses. The present results provide additional support for a previous hypothesis that the anti-CHIKV activity could involve a PKC-dependent mechanism.
authors.affiliation: Laboratoire de Chimie des Produits Naturels, UMR CNRS SPE 6134, University of Corsica , 20250, Corte, France.
authors.forename: Louis-Félix
authors.initials: LF
authors.lastname: Nothias-Scaglia
authors.forename: Pascal
authors.initials: P
authors.lastname: Retailleau
authors.forename: Julien
authors.initials: J
authors.lastname: Paolini
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Vincent
authors.initials: V
authors.lastname: Dumontet
authors.forename: Fanny
authors.initials: F
authors.lastname: Roussi
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.forename: Jean
authors.initials: J
authors.lastname: Costa
authors.forename: Marc
authors.initials: M
authors.lastname: Litaudon
mesh_terms: D018354:Alphavirus Infections / Q000188:drug therapy*; D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D065632:Chikungunya Fever; D002646:Chikungunya virus / Q000187:drug effects*; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D028481:Euphorbia / Q000737:chemistry*; D005602:France; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D012672:Semliki forest virus / Q000187:drug effects; D012845:Sindbis Virus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004224:Diterpenes; C530345:jatrophane