Dysinosin A:  A Novel Inhibitor of Factor VIIa and Thrombin from a New Genus and Species of Australian Sponge of the Family Dysideidae

Carroll, Anthony Richard; Pierens, Gregory K.; Fechner, Gregory Allen; Leone, Priscila de Almeida; Ngo, Anna; Simpson, Moana; Hyde, Edward; Hooper, John N. A.; BostrÖm, S. L.; Müsil, Djordje; Quinn, Ronald J.

doi:10.1021/ja020814a

Cited by 112 publications

(118 citation statements)

References 11 publications

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“…In the case of the thrombin and Factor VIIa inhibitor dysinosin A 49, the structure was determined by detailed NMR studies and its absolute stereochemistry deduced from an X-ray structure of a complex with thrombin [57]. Therefore, the total enantioselective synthesis of dysinosin A 49 provides definitive evidence for its structural and configurational identity [58] (Figure 7.23).…”

Section: Stereochemistrymentioning

confidence: 99%

Nuclear Magnetic Resonance Spectroscopy for Structural Characterization of Bioactive Compounds

Santos

Silva

2014

Comprehensive Analytical Chemistry

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Section: Stereochemistrymentioning

confidence: 99%

Nuclear Magnetic Resonance Spectroscopy for Structural Characterization of Bioactive Compounds

Santos

Silva

2014

Comprehensive Analytical Chemistry

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“…20), from a new sponge family Dysideidae was isolated recently [147]. Dysinosin A is a potent inhibitor of the fVIIa.…”

Section: Natural Products Inhibitors Of Fviia (Paths 'A' and 'B')mentioning

confidence: 99%

Recent Research Developments in the Direct Inhibition of Coagulation Proteinases – Inhibitors of the Initiation Phase

Henry¹,

Desai²

2008

CHAMC

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Physiologic clotting is a defensive action. The new cell-based model of hemostasis proposes three steps -initiation, amplification and propagation -occurring on specific cell surfaces to generate a thrombus in a tightly regulated manner. The initiation phase relies on key players including tissue factor (TF), factor VIIa (fVIIa), platelets, Ca 2+ , phospholipids, and factor X/Xa (fX/fXa). Exposure of TF on sub-endothelial and other blood cells triggers a coagulation response, which may have to be inhibited to prevent a deleterious thrombotic effect. Inhibiting TF-initiated coagulation, akin to 'nipping coagulation in the bud', is predicted to have major advantages, including a more efficient separation of the antithrombotic and hemorrhagic responses. The availability of crystal structures of TF, fVIIa and TFfVIIa complex makes structure-based drug design feasible. Although no initiation phase small molecule inhibitor has reached the clinic as yet, several molecules have displayed promise. We discuss recent results on the discovery of inhibitors of the initiation phase with special emphasis on peptides, peptidomimetics and organic small molecules.Key Words: Anticoagulants, coagulation, factor VIIa, tissue factor, thrombin, factor Xa, Enzyme Inhibition, small molecule inhibitors. CELL-BASED HEMOSTASISPhysiologic clotting is a defensive action preventing excessive loss of blood and infiltration of microbes. The physiologic mechanism that produces this defensive reaction is an enzymatic cascade ( Fig. 1), proposed nearly 50 years ago [1,2]. In vivo, the enzymatic reactions occur on specific cell surfaces. The cell-dependent coagulation cascade is proposed to proceed sequentially in three stepsinitiation, amplification and propagation -on specific cell surfaces to generate a thrombus in a tightly regulated manner [3][4][5]. InitiationTissue factor (TF) is an integral membrane protein present on several extravascular cells [6] and is the most important initiator of coagulation. Under normal conditions, it is sequestered from circulating proteinases, especially factor VII (fVII), thus preventing inappropriate initiation of clotting. Vascular injury exposes TF to blood, resulting in rapid complex formation with free activated fVII (fVIIa) on TF-bearing cells (Fig. 1). It is believed that some fVIIa is always present in blood (~1-2%), which can rapidly interact with TF to initiate clotting. The formation of TF/fVIIa complex activates the circulating factor X (fX) to fXa, the formation of which can induce further production of fVIIa and fXa [7][8][9]. The TF/fVIIa complex can also activate factor IX (fIX) to fIXa [10][11][12], which in turn can result in more fXa. The earliest fXa formed remains localized to the site of TF-bearing cells, yet is free enough to form the prothrombinase complex with factor Va (fVa). The small amount of the prothrombinase complex so formed is responsible for the initial production of thrombin from prothrombin [12]. The in vivo source of the initial fVa needed for the assembly of p...

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“…Within the aeruginosin group, the dysinosins represent a unique subset of dihydroxylated octahydroindole-2-carboxylic acid amides, isolated from the Dysideidae family of marine sponges [167] (Figure 21). The structure and configurational assignment of dysinosin A (92) was achieved through a total synthesis [168] following NMR and X-ray structure work with thrombin.…”

Section: Marine and Freshwater Natural Product Thrombin A C H T U N Gmentioning

confidence: 99%

Structure‐Based Organic Synthesis of Drug Prototypes: A Personal Odyssey

Hanessian¹

2006

ChemMedChem

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Dysinosin A: A Novel Inhibitor of Factor VIIa and Thrombin from a New Genus and Species of Australian Sponge of the Family Dysideidae

Cited by 112 publications

References 11 publications

Nuclear Magnetic Resonance Spectroscopy for Structural Characterization of Bioactive Compounds

Nuclear Magnetic Resonance Spectroscopy for Structural Characterization of Bioactive Compounds

Recent Research Developments in the Direct Inhibition of Coagulation Proteinases – Inhibitors of the Initiation Phase

Structure‐Based Organic Synthesis of Drug Prototypes: A Personal Odyssey

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