Molecular requirements for safer generation of thrombolytics by bioengineering the tissue-type plasminogen activator A chain
Article first published online: 13 MAR 2013
© 2013 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 11, Issue 3, pages 539–546, March 2013
How to Cite
Molecular requirements for safer generation of thrombolytics by bioengineering the tissue-type plasminogen activator A chain. J Thromb Haemost 2013;11:539–46., , , , , .
- Issue published online: 13 MAR 2013
- Article first published online: 13 MAR 2013
- Accepted manuscript online: 10 JAN 2013 04:23AM EST
- Manuscript Accepted: 20 DEC 2012
- Manuscript Received: 20 OCT 2011
- tissue-type plasminogen activator
Thrombolysis with tissue-type plasminogen activator (t-PA) is the only treatment approved for acute ischemic stroke. Although t-PA is an efficient clot lysis enzyme, it also causes damage to the neurovascular unit, including hemorrhagic transformations and neurotoxicity.
On the basis of the mechanism of action of t-PA on neurotoxicity, we aimed at studying the molecular requirements to generate safer thrombolytics.
We produced original t-PA-related mutants, including a non-cleavable single-chain form with restored zymogenicity (sc*-t-PA) and a t-PA modified in the kringle 2 lysine-binding site (K2*-t-PA). Both sc*-t-PA and K2*-t-PA showed fibrinolytic activities similar to that of wild-type t-PA on both euglobulin-containing and plasma-containing clots. In contrast to wild-type t-PA, the two mutants did not promote N-methyl-d-aspartate receptor-mediated neurotoxicity.
We designed t-PA mutants with molecular properties that, in contrast to t-PA, do not induce neurotoxicity.