Dysinosin A: a novel inhibitor of Factor VIIa and thrombin from a new genus and species of Australian sponge of the family Dysideidae

J Am Chem Soc. 2002 Nov 13;124(45):13340-1. doi: 10.1021/ja020814a.

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.

MeSH terms

  • Animals
  • Factor VIIa / antagonists & inhibitors*
  • Humans
  • Hydrogen Bonding
  • Indoles / chemistry*
  • Indoles / isolation & purification
  • Indoles / pharmacology
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Porifera / chemistry*
  • Pyrroles / chemistry*
  • Pyrroles / isolation & purification
  • Pyrroles / pharmacology
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / isolation & purification
  • Serine Proteinase Inhibitors / pharmacology
  • Spectrometry, Mass, Electrospray Ionization
  • Stereoisomerism
  • Thrombin / antagonists & inhibitors*

Substances

  • Indoles
  • Pyrroles
  • Serine Proteinase Inhibitors
  • dysinosin A
  • Factor VIIa
  • Thrombin