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A novel variant of t-PA resistant to plasminogen activator inhibitor-1; expression in CHO cells based on In Silico experiments

Fatemeh Davami|Soroush Sardari|Keivan Majidzadeh-A|Mahdi Hemayatkar|Farzaneh Barkhordari|Somayeh Enayati|Ahmad Adeli|Fereidoun Mahboudi
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2011.01|BMB Reports|제44권 제1호|pp. 34-39

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키워드

Amidolytic activityChinese hamster ovary (CHO)In SilicoPlasminogen activator inhibitor-1 (PAI-1)Tissue plasminogen activator (t-PA)
주제분류화학

초록

Resistance to PAI-1 is a factor which confers clinical benefits in thrombolytic therapy. The only US FDA approved PAI-1 resistant drug is TenecteplaseⓇ. Deletion variants of t-PA have the advantage of fewer disulfide bonds in addition to higher plasma half lives. A new variant was developed by deletion of the first three domains in t-PA in addition to substitution of KHRR 128-131 amino acids with AAAA in truncated t-PA. The specific activity of this new variant, 570 IU/μg, was found to be similar to those found in full length t-PA (AlteplaseⓇ), 580IU/μg. A 65% and 85% residual activity after inhibition by rPAI-1 was observed for full length and truncated-mutant form,respectively. This new variant as the first PAI-1 resistant truncated t-PA may offer more advantages in clinical conditions in which high PAI-1 levels makes the thrombolytic system prone to re-occlusion. [BMB reports 2011; 44(1): 34-39]

Abstract

Resistance to PAI-1 is a factor which confers clinical benefits in thrombolytic therapy. The only US FDA approved PAI-1 resistant drug is TenecteplaseⓇ. Deletion variants of t-PA have the advantage of fewer disulfide bonds in addition to higher plasma half lives. A new variant was developed by deletion of the first three domains in t-PA in addition to substitution of KHRR 128-131 amino acids with AAAA in truncated t-PA. The specific activity of this new variant, 570 IU/μg, was found to be similar to those found in full length t-PA (AlteplaseⓇ), 580IU/μg. A 65% and 85% residual activity after inhibition by rPAI-1 was observed for full length and truncated-mutant form,respectively. This new variant as the first PAI-1 resistant truncated t-PA may offer more advantages in clinical conditions in which high PAI-1 levels makes the thrombolytic system prone to re-occlusion. [BMB reports 2011; 44(1): 34-39]

참고문헌 (38)

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