Metalyse® is a 527 amino acid glycoprotein produced by modifying the complementary DNA (cDNA) for natural human t-PA at three key sites using an established mammalian cell line (Chinese Hamster Ovary Cells). Hepatic elimination is the main clearance mechanism. Natural human t-PA has a modular structure consisting of five domains: a "finger" domain, an epidermal growth factor region, two "kringle" structures, and a serine protease domain.

In comparison with human t-PA Metalyse® is modified by:

  • substitution of threonine-103 by asparagine, adding a new glycosylation site on kringle-1, which decreases the rates of clearance and fibrin binding.
  • substitution of asparagine-117 by glutamine, removing the existing glycosylation on kringle-1, decreasing the rate of clearance and restores fibrin binding in combination with Thr-103 àASN.
  • substitution of one lysine, one histidine and two arginines by four alanines at positions 296-299, increasing fibrin specificity and giving higher resistance to the naturally occurring inhibitor PAI-1.

These key site modifications have been shown in animal models to bring the following advantages in comparison to wild type plasminogen activator:

  • a 4-8-fold slower plasma clearance in 5 animal species.
  • a 14-fold higher fibrin specifity than that of alteplase.
  • an 80-fold greater resistance to inhibition by plasminogen activator inhibitor 1 (PAI-1), which is secreted by activated platelets.
  • clot lysis: arterial venous shunt models in rabbits indicate that bolus tenecteplase induces 50% lysis in one-third the time required by alteplase infusion.
  • platelet aggregation: at the doses examined, tenecteplase produces little or no potentiation of collagen-sensitised platelet aggregation, suggesting a decreased risk of reocclusion after thrombolysis.

In vivo performance:

  • in rabbits with thrombotically occluded arteries, tenecteplase produced faster and more complete recanalisation than alteplase without increasing systemic plasmin generation or peripheral bleeding.


Tenecteplase Biochemical structure of Tenecteplase glycoprotein

Molecular modifications in the tenecteplase molecule compared to alteplase

Molecular modifications in the tenecteplase molecule compared to alteplase Table showing amino acid substitutions in Tenecteplase in comparison with alteplase and its effect on mode of action

Bioengeneering Part 1

Bioengeneering Part 1


Bioengeneering Part 2

Bioengeneering Part 2

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