title: Dysinosin A: a novel inhibitor of Factor VIIa and thrombin from a new genus and species of Australian sponge of the family Dysideidae.
abstract: A new marine natural product dysinosin A 1 has been isolated from a new genus and species of sponge of the family Dysideidae found near Lizard Island, North Queensland, Australia. Dysinosin A is a potent inhibitor of the blood coagulation cascade factor VIIa and an inhibitor of the serine protease thrombin. Among the distinctive features of dysinosin A are the presence of a 5,6-dihydroxy-octahydroindole-2-carboxylic acid, 3-amino-ethyl 1-N-amidino-Delta-3-pyrroline, a sulfated glyceric acid, and d-leucine, assembled through three peptidic linkages. Dysinosin A inhibited factor VIIa at a Ki of 108 nM and thrombin at a Ki of 452 nM. The identification of the 1-N-amidino-Delta-3-pyrroline and 5,6-dihydroxy-octahydroindole-2-carboxylic acid as P1 and P2 moieties respectively, should pave the way for the design and synthesis of new structure-based inhibitors.
authors.affiliation: AstraZeneca R&D Griffith University, Brisbane, Australia 4111.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Carroll
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Pierens
authors.forename: Greg
authors.initials: G
authors.lastname: Fechner
authors.forename: Priscila
authors.initials: P
authors.lastname: De Almeida Leone
authors.forename: Anna
authors.initials: A
authors.lastname: Ngo
authors.forename: Moana
authors.initials: M
authors.lastname: Simpson
authors.forename: Edward
authors.initials: E
authors.lastname: Hyde
authors.forename: John N A
authors.initials: JN
authors.lastname: Hooper
authors.forename: Stig-Lennart
authors.initials: SL
authors.lastname: Boström
authors.forename: Djordje
authors.initials: D
authors.lastname: Musil
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Quinn
mesh_terms: D000818:Animals; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011161:Porifera / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D007211:Indoles; D011758:Pyrroles; D015842:Serine Proteinase Inhibitors; C470588:dysinosin A; D015942:Factor VIIa; D013917:Thrombin