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Identification
Name Tenecteplase
Accession Number DB00031 (BIOD00019, BTD00019)
Type biotech
Groups approved
Description

Tissue plasminogen activator (tPA). Tenecteplase is a 527 amino acid glycoprotein developed by introducing the following modifications to the complementary DNA (cDNA) for natural human tPA: a substitution of threonine 103 with asparagine, and a substitution of asparagine 117 with glutamine, both within the kringle 1 domain, and a tetra-alanine substitution at amino acids 296-299 in the protease domain.
Protein structure Db00031
Display: 3D Structure
Protein chemical formula C2561H3919N747O781S40
Protein average weight 58951.2000
Sequences 
>DB00031 sequence
SYQVICRDEKTQMIYQQHQSWLRPVLRSNRVEYCWCNSGRAQCHSVPVKSCSEPRCFNGG
TCQQALYFSDFVCQCPEGFAGKCCEIDTRATCYEDQGISYRGNWSTAESGAECTQWNSSA
LAQKPYSGRRPDAIRLGLGNHNYCRNPDRDSKPWCYVFKAGKYSSEFCSTPACSEGNSDC
YFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSAQALGLGKHNYCRNPDGDAK
PWCHVLKNRRLTWEYCDVPSCSTCGLRQYSQPQFRIKGGLFADIASHPWQAAAAAKHRRS
PGERFLCGGILISSCWILSAAHCFQERFPPHHLTVILGRTYRVVPGEEEQKFEVEKYIVH
KEFDDDTYDNDIALLQLKSDSSRCAQESSVVRTVCLPPADLQLPDWTECELSGYGKHEAL
SPFYSERLKEAHVRLYPSSRCTSQHLLNRTVTDNMLCAGDTRSGGPQANLHDACQGDSGG
PLVCLNDGRMTLVGIISWGLGCGQKDVPGVYTKVTNYLDWIRDNMRP

FASTA
Synonyms
t- PA
t-plasminogen activator
Tissue-type plasminogen activator precursor
tPA
Salts Not Available
Brand names
Name Company
TNKase (Genentech Inc)
Brand mixtures Not Available
Categories
  • Thrombolytic Agents
CAS number 191588-94-0
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication For treatment of myocardial infarction and lysis of intracoronary emboli
Pharmacodynamics Tenecteplase is a fibrin-specific tissue-plasminogen activator. It binds to fibrin rich clots and cleaves the Arg/Val bond in plasminogen to form plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action. This helps eliminate blood clots or arterial blockages that cause myocardial infarction.
Mechanism of action Tenecteplase binds to fibrin rich clots via the fibronectin finger-like domain and the Kringle 2 domain. The protease domain then cleaves the Arg/Val bond in plasminogen to form plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action.
Absorption Not Available
Volume of distribution Not Available
Protein binding Not Available
Metabolism Not Available
Route of elimination Not Available
Half life 1.9 hours (mammalian reticulocytes, in vitro) >20 hours (yeast, in vivo) >10 hours (Escherichia coli, in vivo)
Clearance
  • 99 – 119 mL/min [acute myocardial infarction patients]
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00283 Tenecteplase Pathway SMP00283
Pharmacoeconomics
Manufacturers Not Available
Packagers
Dosage forms
Form Route Strength
Powder, for solution Intravenous
Prices
Unit description Cost Unit
Tnkase 50 mg kit 3238.76 USD kit
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
Canada 2129660 2005-06-28 2013-05-28
Canada 1341432 2003-06-17 2020-06-17
Properties
State liquid
Experimental Properties
Property Value Source
melting point 60 °C Novokhatny, V.V. et al., J. Biol. Chem. 266:12994-123002 (1991)
hydrophobicity -0.528 Not Available
isoelectric point 7.61 Not Available
References
Synthesis Reference Not Available
General Reference
  1. Gurbel PA, Hayes K, Bliden KP, Yoho J, Tantry US: The platelet-related effects of tenecteplase versus alteplase versus reteplase. Blood Coagul Fibrinolysis. 2005 Jan;16(1):1-7. Pubmed
  2. Melzer C, Richter C, Rogalla P, Borges AC, Theres H, Baumann G, Laule M: Tenecteplase for the treatment of massive and submassive pulmonary embolism. J Thromb Thrombolysis. 2004 Aug;18(1):47-50. Pubmed
  3. Ohman EM, Van de Werf F, Antman EM, Califf RM, de Lemos JA, Gibson CM, Oliverio RL, Harrelson L, McCabe C, DiBattiste P, Braunwald E: Tenecteplase and tirofiban in ST-segment elevation acute myocardial infarction: results of a randomized trial. Am Heart J. 2005 Jul;150(1):79-88. Pubmed
  4. De Luca G, Suryapranata H, Chiariello M: Tenecteplase followed by immediate angioplasty is more effective than tenecteplase alone for people with STEMI. Commentary. Evid Based Cardiovasc Med. 2005 Dec;9(4):284-7. Epub 2005 Nov 2. Pubmed
  5. : Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): randomised trial. Lancet. 2006 Feb 18;367(9510):569-78. Pubmed
External Links
Resource Link
UniProt P00750 Link_out
Genbank L00153 Link_out
PharmGKB PA164776757 Link_out
Drug Product Database 2244826 Link_out
RxList http://www.rxlist.com/cgi/generic2/tenecteplase.htm Link_out
Drugs.com http://www.drugs.com/mtm/tenecteplase.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Tenecteplase Link_out
ATC Codes
  • B01AD11
AHFS Codes
  • 20:12.20
PDB Entries
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Aprotinin Aprotonin may antagonize the effect of Tenecteplase. Monitor for decreased effects of Tenecteplase.
Drotrecogin alfa Increased risk of bleeding.
Ginkgo biloba Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.
Ginseng Increased risk of bleeding.
Ticlopidine Increased bleeding risk. Monitor for signs of bleeding.
Food Interactions Not Available
Targets

1. Plasminogen

Pharmacological action: yes
Actions: activator

Angiostatin is an angiogenesis inhibitor that blocks neovascularization and growth of experimental primary and metastatic tumors in vivo

Organism class: human
UniProt ID: P00747 Link_out
Gene: PLG Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Longstaff C, Williams S, Thelwell C: Fibrin binding and the regulation of plasminogen activators during thrombolytic therapy. Cardiovasc Hematol Agents Med Chem. 2008 Jul;6(3):212-23. Pubmed
  2. Melandri G, Vagnarelli F, Calabrese D, Semprini F, Nanni S, Branzi A: Review of tenecteplase (TNKase) in the treatment of acute myocardial infarction. Vasc Health Risk Manag. 2009;5(1):249-56. Epub 2009 Apr 8. Pubmed
  3. Hilleman DE, Tsikouris JP, Seals AA, Marmur JD: Fibrinolytic agents for the management of ST-segment elevation myocardial infarction. Pharmacotherapy. 2007 Nov;27(11):1558-70. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Fibrinogen alpha chain

Pharmacological action: yes

Fibrinogen has a double function:yielding monomers that polymerize into fibrin and acting as a cofactor in platelet aggregation

Organism class: human
UniProt ID: P02671 Link_out
Gene: FGA Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Melandri G, Vagnarelli F, Calabrese D, Semprini F, Nanni S, Branzi A: Review of tenecteplase (TNKase) in the treatment of acute myocardial infarction. Vasc Health Risk Manag. 2009;5(1):249-56. Epub 2009 Apr 8. Pubmed
  2. Longstaff C, Williams S, Thelwell C: Fibrin binding and the regulation of plasminogen activators during thrombolytic therapy. Cardiovasc Hematol Agents Med Chem. 2008 Jul;6(3):212-23. Pubmed
  3. Hilleman DE, Tsikouris JP, Seals AA, Marmur JD: Fibrinolytic agents for the management of ST-segment elevation myocardial infarction. Pharmacotherapy. 2007 Nov;27(11):1558-70. Pubmed

3. Urokinase plasminogen activator surface receptor

Pharmacological action: unknown

Acts as a receptor for urokinase plasminogen activator. Plays a role in localizing and promoting plasmin formation. Mediates the proteolysis-independent signal transduction activation effects of U-PA. It is subject to negative-feedback regulation by U-PA which cleaves it into an inactive form

Organism class: human
UniProt ID: Q03405 Link_out
Gene: PLAUR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Maupas-Schwalm F, Auge N, Robinet C, Cambus JP, Parsons SJ, Salvayre R, Negre-Salvayre A: The sphingomyelin/ceramide pathway is involved in ERK1/2 phosphorylation, cell proliferation, and uPAR overexpression induced by tissue-type plasminogen activator. FASEB J. 2004 Sep;18(12):1398-400. Epub 2004 Jul 1. Pubmed
  2. Bankl HC, Samorapoompichit P, Pikula B, Latinovic L, Bankl H, Lechner K, Valent P: Characterization of human prostate mast cells and their increase in periprostatic vein thrombosis. Am J Clin Pathol. 2001 Jul;116(1):97-106. Pubmed
  3. Ferrier CM, Van Geloof WL, Straatman H, Van De Molengraft FJ, Van Muijen GN, Ruiter DJ: Spitz naevi may express components of the plasminogen activation system. J Pathol. 2002 Sep;198(1):92-9. Pubmed

4. Plasminogen activator inhibitor 1

Pharmacological action: unknown

This inhibitor acts as 'bait' for tissue plasminogen activator, urokinase, and protein C. Its rapid interaction with TPA may function as a major control point in the regulation of fibrinolysis

Organism class: human
UniProt ID: P05121 Link_out
Gene: SERPINE1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lindberg P, Kinnby B, Lecander I, Lang NP, Matsson L: Increasing expression of tissue plasminogen activator and plasminogen activator inhibitor type 2 in dog gingival tissues with progressive inflammation. Arch Oral Biol. 2001 Jan;46(1):23-31. Pubmed
  2. Hattori M, Azami Y: Searching for preventive measures of cardiovascular events in aged Japanese taxi drivers—the daily rhythm of cardiovascular risk factors during a night duty day. J Hum Ergol (Tokyo). 2001 Dec;30(1-2):321-6. Pubmed
  3. Hilleman DE, Tsikouris JP, Seals AA, Marmur JD: Fibrinolytic agents for the management of ST-segment elevation myocardial infarction. Pharmacotherapy. 2007 Nov;27(11):1558-70. Pubmed

5. Plasminogen activator inhibitor 2

Pharmacological action: unknown

Inhibits urokinase-type plasminogen activator. The monocyte derived PAI-2 is distinct from the endothelial cell- derived PAI-1

Organism class: human
UniProt ID: P05120 Link_out
Gene: SERPINB2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Verkleij-Hagoort AC, Ursem NT, Hop WC, Geurts-Moespot A, Steegers EA, Sweep FC, Steegers-Theunissen RP: Complex congenital malformations and the impact of the plasminogen activator system and beta-hCG in amniotic fluid. Eur J Obstet Gynecol Reprod Biol. 2006 Nov 30;. Pubmed
  2. Bremer HA, Brommer EJ, Wallenburg HC: Effects of labor and delivery on fibrinolysis. Eur J Obstet Gynecol Reprod Biol. 1994 Jun 30;55(3):163-8. Pubmed
  3. Stump DC, Thienpont M, Collen D: Purification and characterization of a novel inhibitor of urokinase from human urine. Quantitation and preliminary characterization in plasma. J Biol Chem. 1986 Sep 25;261(27):12759-66. Pubmed

6. Tetranectin

Pharmacological action: unknown

Tetranectin binds to plasminogen and to isolated kringle 4. May be involved in the packaging of molecules destined for exocytosis

Organism class: human
UniProt ID: P05452 Link_out
Gene: CLEC3B Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Westergaard UB, Andersen MH, Heegaard CW, Fedosov SN, Petersen TE: Tetranectin binds hepatocyte growth factor and tissue-type plasminogen activator. Eur J Biochem. 2003 Apr;270(8):1850-4. Pubmed
  2. Kamper EF, Kopeikina LT, Koutsoukos V, Stavridis J: Plasma tetranectin levels and disease activity in patients with rheumatoid arthritis. J Rheumatol. 1997 Feb;24(2):262-8. Pubmed
  3. Vuckovic B, Deric M: [Lipoprotein(a): a link between thrombogenesis and atherogenesis] Med Pregl. 2007 Jan-Feb;60(1-2):37-41. Pubmed

7. Keratin, type II cytoskeletal 8

Pharmacological action: unknown

Together with KRT19, helps to link the contractile apparatus to dystrophin at the costameres of striated muscle

Organism class: human
UniProt ID: P05787 Link_out
Gene: KRT8 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kralovich KR, Li L, Hembrough TA, Webb DJ, Karns LR, Gonias SL: Characterization of the binding sites for plasminogen and tissue-type plasminogen activator in cytokeratin 8 and cytokeratin 18. J Protein Chem. 1998 Nov;17(8):845-54. Pubmed
  2. Hembrough TA, Kralovich KR, Li L, Gonias SL: Cytokeratin 8 released by breast carcinoma cells in vitro binds plasminogen and tissue-type plasminogen activator and promotes plasminogen activation. Biochem J. 1996 Aug 1;317 ( Pt 3):763-9. Pubmed
  3. Hembrough TA, Li L, Gonias SL: Cell-surface cytokeratin 8 is the major plasminogen receptor on breast cancer cells and is required for the accelerated activation of cell-associated plasminogen by tissue-type plasminogen activator. J Biol Chem. 1996 Oct 11;271(41):25684-91. Pubmed

8. Annexin A2

Pharmacological action: unknown

Calcium-regulated membrane-binding protein whose affinity for calcium is greatly enhanced by anionic phospholipids. It binds two calcium ions with high affinity

Organism class: human
UniProt ID: P07355 Link_out
Gene: ANXA2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Diaz VM, Hurtado M, Thomson TM, Reventos J, Paciucci R: Specific interaction of tissue-type plasminogen activator (t-PA) with annexin II on the membrane of pancreatic cancer cells activates plasminogen and promotes invasion in vitro. Gut. 2004 Jul;53(7):993-1000. Pubmed
  2. Kang HM, Choi KS, Kassam G, Fitzpatrick SL, Kwon M, Waisman DM: Role of annexin II tetramer in plasminogen activation. Trends Cardiovasc Med. 1999 Apr-May;9(3-4):92-102. Pubmed
  3. MacLeod TJ, Kwon M, Filipenko NR, Waisman DM: Phospholipid-associated annexin A2-S100A10 heterotetramer and its subunits: characterization of the interaction with tissue plasminogen activator, plasminogen, and plasmin. J Biol Chem. 2003 Jul 11;278(28):25577-84. Epub 2003 Apr 30. Pubmed

9. Calreticulin

Pharmacological action: unknown

Molecular calcium binding chaperone promoting folding, oligomeric assembly and quality control in the ER via the calreticulin/calnexin cycle. This lectin interacts transiently with almost all of the monoglucosylated glycoproteins that are synthesized in the ER. Interacts with the DNA-binding domain of NR3C1 and mediates its nuclear export

Organism class: human
UniProt ID: P27797 Link_out
Gene: CALR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Allen S, Bulleid NJ: Calnexin and calreticulin bind to enzymically active tissue-type plasminogen activator during biosynthesis and are not required for folding to the native conformation. Biochem J. 1997 Nov 15;328 ( Pt 1):113-9. Pubmed

10. Calnexin

Pharmacological action: unknown

Calcium-binding protein that interacts with newly synthesized glycoproteins in the endoplasmic reticulum. It may act in assisting protein assembly and/or in the retention within the ER of unassembled protein subunits. It seems to play a major role in the quality control apparatus of the ER by the retention of incorrectly folded proteins

Organism class: human
UniProt ID: P27824 Link_out
Gene: CANX Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Allen S, Bulleid NJ: Calnexin and calreticulin bind to enzymically active tissue-type plasminogen activator during biosynthesis and are not required for folding to the native conformation. Biochem J. 1997 Nov 15;328 ( Pt 1):113-9. Pubmed

11. Low-density lipoprotein receptor-related protein 1

Pharmacological action: unknown

Required for early embryonic development. Involved in the plasma clearance of chylomicron remnants and activated alpha 2-macroglobulin, as well as the local metabolism of complexes between plasminogen activators and their endogenous inhibitors. May modulate APP metabolism, kinase-dependent intracellular signaling, neuronal calcium signaling as well as neurotransmission

Organism class: human
UniProt ID: Q07954 Link_out
Gene: LRP1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Moestrup SK, Nielsen S, Andreasen P, Jorgensen KE, Nykjaer A, Roigaard H, Gliemann J, Christensen EI: Epithelial glycoprotein-330 mediates endocytosis of plasminogen activator-plasminogen activator inhibitor type-1 complexes. J Biol Chem. 1993 Aug 5;268(22):16564-70. Pubmed
  2. Nykjaer A, Petersen CM, Moller B, Jensen PH, Moestrup SK, Holtet TL, Etzerodt M, Thogersen HC, Munch M, Andreasen PA, et al.: Purified alpha 2-macroglobulin receptor/LDL receptor-related protein binds urokinase.plasminogen activator inhibitor type-1 complex. Evidence that the alpha 2-macroglobulin receptor mediates cellular degradation of urokinase receptor-bound complexes. J Biol Chem. 1992 Jul 25;267(21):14543-6. Pubmed
  3. Hu K, Yang J, Tanaka S, Gonias SL, Mars WM, Liu Y: Tissue-type plasminogen activator acts as a cytokine that triggers intracellular signal transduction and induces matrix metalloproteinase-9 gene expression. J Biol Chem. 2006 Jan 27;281(4):2120-7. Epub 2005 Nov 22. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on September 29, 2010 14:34