Dysinosin A: a novel inhibitor of Factor VIIa and thrombin from a new genus and species of Australian sponge of the family Dysideidae.
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.
Carroll
Anthony R
AR
AstraZeneca R&D Griffith University, Brisbane, Australia 4111.
Pierens
Gregory K
GK
Fechner
Greg
G
De Almeida Leone
Priscila
P
Ngo
Anna
A
Simpson
Moana
M
Hyde
Edward
E
Hooper
John N A
JN
Boström
Stig-Lennart
SL
Musil
Djordje
D
Quinn
Ronald J
RJ
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*
D007211:Indoles; D011758:Pyrroles; D015842:Serine Proteinase Inhibitors; C470588:dysinosin A; D015942:Factor VIIa; D013917:Thrombin