Thrombolysis with a snake venom protease in a rat model of venous thrombosis

Willis, T. W.; Tu, Anthony T.; Miller, Charles W.

doi:10.1016/0049-3848(89)90112-6

Cited by 31 publications

(5 citation statements)

References 15 publications

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“…At a relatively high concentration, CAMP-2 was also found to inhibit human platelet aggregation. These functions of CAMP-2 are very similar to the ones that have been reported for atroxase (a non-haemolytic protease with fibrin(ogen)olytic activity) [20,23]. Although the complete sequence of CAMP-2 was not obtained in this study, based on the mass spectrometry and functional data, this protein is highly similar, if not identical, to atroxase.…”

Section: Discussionsupporting

confidence: 83%

“…The peptide sequences resulting from the mass spectrometry covered 52.2% of atroxase, suggesting that the purified protein is highly likely to be atroxase although we cannot confirm this due to the lack of complete sequencing from this study. However, these data confirm that the purified protein is a PI SVMP with a molecular weight of 23 kDa, and it is likely to be atroxase, which was previously purified and characterised as a non-haemorrhagic protease with fibrin(ogen)olytic activities [20][21][22][23].…”

Section: Purification and Identification Of Camp-2supporting

confidence: 72%

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Repurposing Cancer Drugs Batimastat and Marimastat to Inhibit the Activity of a Group I Metalloprotease from the Venom of the Western Diamondback Rattlesnake, Crotalus atrox

Layfield

Williams

Ravishankar

et al. 2020

Toxins

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Snakebite envenomation causes over 140,000 deaths every year, predominantly in developing countries. As a result, it is one of the most lethal neglected tropical diseases. It is associated with incredibly complex pathophysiology due to the vast number of unique toxins/proteins present in the venoms of diverse snake species found worldwide. Here, we report the purification and functional characteristics of a Group I (PI) metalloprotease (CAMP-2) from the venom of the western diamondback rattlesnake, Crotalus atrox. Its sensitivity to matrix metalloprotease inhibitors (batimastat and marimastat) was established using specific in vitro experiments and in silico molecular docking analysis. CAMP-2 shows high sequence homology to atroxase from the venom of Crotalus atrox and exhibits collagenolytic, fibrinogenolytic and mild haemolytic activities. It exerts a mild inhibitory effect on agonist-induced platelet aggregation in the absence of plasma proteins. Its collagenolytic activity is completely inhibited by batimastat and marimastat. Zinc chloride also inhibits the collagenolytic activity of CAMP-2 by around 75% at 50 μM, while it is partially potentiated by calcium chloride. Molecular docking studies have demonstrated that batimastat and marimastat are able to bind strongly to the active site residues of CAMP-2. This study demonstrates the impact of matrix metalloprotease inhibitors in the modulation of a purified, Group I metalloprotease activities in comparison to the whole venom. By improving our understanding of snake venom metalloproteases and their sensitivity to small molecule inhibitors, we can begin to develop novel and improved treatment strategies for snakebites.

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Section: Discussionsupporting

confidence: 83%

Section: Purification and Identification Of Camp-2supporting

confidence: 72%

Repurposing Cancer Drugs Batimastat and Marimastat to Inhibit the Activity of a Group I Metalloprotease from the Venom of the Western Diamondback Rattlesnake, Crotalus atrox

Layfield

Williams

Ravishankar

et al. 2020

Toxins

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“…Recent interest has been generated in snake venom direct-acting fibrinolytic metalloproteinases because of their clinical potential for the treatment of occlusive vascular disease. Several of these enzymes have been tested in vivo with promising results (23,47,55,77,79,101). These studies revealed that the highly purified fibrinolytic snake venom enzymes produced consistent thrombolysis.…”

mentioning

confidence: 99%

Snake Venom Fibrinogenolytic and Fibrinolytic Enzymes: An Updated Inventory

Markland

1998

Thromb Haemost

103

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“…In addition to their fibrinogen-degrading properties, venoms derived from various rattlesnake species (Crotalus species) have been demonstrated to have thrombolytic properties in vivo in rodent models [1][2][3], and specifically have been found to enzymatically digest two key antifibrinolytic enzymes in vitro, alpha-2-antiplasmin and alpha-2-macroglobulin [4,5]. Thus, it would be anticipated that degradation of these two enzymes would enhance endogenous fibrinolysis, significantly contributing to the coagulopathy associated with envenomation with Crotalus species venom.…”

Section: Introductionmentioning

confidence: 99%

Iron and carbon monoxide attenuate Crotalus atrox venom-enhanced tissue-type plasminogen activator-initiated fibrinolysis

Nielsen

Boyer²,

Matika³

et al. 2016

Blood Coagulation &Amp; Fibrinolysis

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In addition to degrading fibrinogen as a source of consumptive coagulopathy, rattlesnake venom has also been demonstrated to enhance fibrinolysis and degrade alpha-2-antiplasmin. The goals of this investigation was to characterize the kinetic fibrinolytic profile of Crotalus atrox venom in the absence and presence of tissue-type plasminogen activator (tPA), and to also ascertain if iron and carbon monoxide (CO, a positive modulator of alpha-2-antiplasmin) could attenuate venom-enhanced fibrinolysis. Utilizing thrombelastographic methods, the coagulation and fibrinolytic kinetic profiles of human plasma exposed to C. atrox venom (0-2 μg/ml) were determined in the absence or presence of tPA (0-100 IU/ml). Then, either separately or in combination, plasma was exposed to iron (ferric chloride, 10 μmol/l) or CO (carbon monoxide-releasing molecule-2, 100 μmol/l) prior to incubation with venom; the plasma sample was subsequently subjected to thrombelastographic analysis with addition of tPA. Venom exposure in the absence of tPA did not result in detectable fibrinolysis. In the presence of tPA, venom markedly enhanced fibrinolysis. Iron and CO, markedly attenuated venom enhancement of fibrinolysis. C. atrox venom enhances tPA-mediated fibrinolysis, and interventions that enhance/protect alpha-2-antiplasmin activity significantly attenuate venom-enhanced fibrinolysis. Future preclinical investigation is required to determine if iron and CO can attenuate venom-mediated degradation of alpha-2-antiplasmin-dependent fibrinolytic resistance.

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Thrombolysis with a snake venom protease in a rat model of venous thrombosis

Cited by 31 publications

References 15 publications

Repurposing Cancer Drugs Batimastat and Marimastat to Inhibit the Activity of a Group I Metalloprotease from the Venom of the Western Diamondback Rattlesnake, Crotalus atrox

Repurposing Cancer Drugs Batimastat and Marimastat to Inhibit the Activity of a Group I Metalloprotease from the Venom of the Western Diamondback Rattlesnake, Crotalus atrox

Snake Venom Fibrinogenolytic and Fibrinolytic Enzymes: An Updated Inventory

Iron and carbon monoxide attenuate Crotalus atrox venom-enhanced tissue-type plasminogen activator-initiated fibrinolysis

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