title: Thalassiolins A-C: new marine-derived inhibitors of HIV cDNA integrase.
abstract: Human immunodeficiency virus (HIV) replication requires integration of viral cDNA into the host genome, a process mediated by the viral enzyme integrase. We describe a new series of HIV integrase inhibitors, thalassiolins A-C (1-3), isolated from the Caribbean sea grass Thalassia testudinum. The thalassiolins are distinguished from other flavones previously studied by the substitution of a sulfated beta-D-glucose at the 7-position, a substituent that imparts increased potency against integrase in biochemical assays. The most active of these molecules, thalassiolin A (1), displays in vitro inhibition of the integrase catalyzed strand transfer reaction (IC50=0.4 microM) and an antiviral IC50 of 30 microM. Molecular modeling studies indicate a favorable binding mode is probable at the catalytic core domain of HIV-1 integrase.
authors.affiliation: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California-San Diego, La Jolla, CA 92093, USA. drowley@uri.edu
authors.forename: David C
authors.initials: DC
authors.lastname: Rowley
authors.forename: Mark S T
authors.initials: MS
authors.lastname: Hansen
authors.forename: Denise
authors.initials: D
authors.lastname: Rhodes
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Sotriffer
authors.forename: Haihong
authors.initials: H
authors.lastname: Ni
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.forename: William
authors.initials: W
authors.lastname: Fenical
mesh_terms: D001665:Binding Sites; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D018076:DNA, Complementary / Q000187:drug effects*; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy; D019427:HIV Integrase / Q000187:drug effects*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D031321:Hydrocharitaceae / Q000737:chemistry*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D018076:DNA, Complementary; D005419:Flavonoids; D019428:HIV Integrase Inhibitors; D007202:Indicators and Reagents; C471627:Thalassiolin C; C471628:thalassiolin A; C471629:thalassiolin B; D019427:HIV Integrase