2013生物药物概况.pptVIP

* Lecture Notes Several molecules have been developed that are variants of naturally occurring t-PA. TNK has nearly the same general amino acid sequence as naturally occurring t-PA, but has been altered in 3 locations. The molecule consists of several morphologically distinct regions with identifiable functions. The fibronectin (fingerlike) domain—responsible for high-affinity fibrin binding. The kringle 1 and epidermal growth factors—account for receptor binding in the liver and rapid clearance from the plasma. The kringle 2 domain—associated with lysine binding and accelerates conversion of plasminogen to plasmin. The protease domain-plasminogen-specific and contains the binding sites for plasminogen activator inhibitor (PAI)-1. t-PA is rapidly cleared from the circulation with an elimination half-life of less than 5 minutes; despite this short half-life, t-PA continues to exert fibrinolytic action at the site of the thrombus for at least 7 hours. (Eisenberg et al, 1987) * Lecture Notes The drug tPA has been altered in 3 domains (the T, N, and K domains) to yield the name TNK. The fibronectin finger region is responsible for the high affinity fibrin binding. The epidermal growth factor region contributes to liver plasma clearance. Kringle 1 is associated with receptor binding and contributes in a major way to fibrin specificity. Additionally, kringle 1 is involved in plasma clearance. The kringle 2 region is involved in low-affinity fibrin binding. Protease domain is the site of enzymatic activity that cleaves the plasminogen to plasmin. PAI-1 inhibition takes place here. The TNK-tPA molecule includes 3 substitution mutations, which enhance its fibrin specificity, prolong its half-life, and greatly increase resistance to PAI-1. The name TNK reflects the fact that three domains (the T, N, and K domains) have been altered. At the T domain, threonine is replaced with asparagine on kringle 1 resulting in slower plasma clearance and thus, a longer half-life compared w