Improved antithrombotic activity and diminished bleeding side effect of a PEGylated αiIbβ3 antagonist, disintegrin

Chun Chieh Hsu, Woei-Jer Chuang, Ching Hu Chung, Chien Hsin Chang, Hui Chin Peng, Tur Fu Huang

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Introduction The applicability of protein drugs is confined by protein degradation and rapid elimination. PEGylation of polypeptides improves protein stability by sterically obstructing the degradation by serum proteases and reduces renal clearance by the increased mass. Experimental approach We compared the antithrombotic activities of intact rhodostomin (Rn) and PEGylated rhodostomin (PRn) both in vitro and in vivo systems. In addition, the functional half-life in inhibiting platelet aggregation and the tendency in causing bleeding side effect were investigated. Results Rn and PRn both potently inhibited human and mouse platelet aggregation induced by collagen, thrombin or ADP in vitro with a similar IC50 around 60-100 nM. Rotational thromboelastometry assay indicated that PRn was more effective than Rn in preventing clot formation in human whole blood. In platelet-rich plasma from mice injected with Rn or PRn, the inhibitory effects on collagen-induced platelet aggregation were also comparable, but Rn caused higher bleeding tendency. In ferric chloride-induced arterial thrombosis, Rn and PRn significantly prolonged occlusion time at high dosage (0.2 μg/g). However, PRn obviously prolonged the occlusion time even given at a lower dosage (0.06 μg/g). The functional half-life assay revealed that PEGylation prolonged the in vivo half-life of Rn. Conclusions PRn exhibits higher antithrombotic potency and longer half-life in vivo as compared with native Rn on a molar basis. In addition, PRn exhibits a better safety profile at an efficacious antithrombotic dose in vivo. Therefore, PEGylation may be one of the ideal options in modifying disintegrin derivatives as the safe therapeutic agents for integrin-related diseases.

Original languageEnglish
Pages (from-to)3-10
Number of pages8
JournalThrombosis Research
Volume143
DOIs
Publication statusPublished - 2016 Jul 1

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Disintegrins
Hemorrhage
Half-Life
Platelet Aggregation
rhodostomin
Collagen
Thrombelastography
Platelet-Rich Plasma
Protein Stability

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

Hsu, Chun Chieh ; Chuang, Woei-Jer ; Chung, Ching Hu ; Chang, Chien Hsin ; Peng, Hui Chin ; Huang, Tur Fu. / Improved antithrombotic activity and diminished bleeding side effect of a PEGylated αiIbβ3 antagonist, disintegrin. In: Thrombosis Research. 2016 ; Vol. 143. pp. 3-10.
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abstract = "Introduction The applicability of protein drugs is confined by protein degradation and rapid elimination. PEGylation of polypeptides improves protein stability by sterically obstructing the degradation by serum proteases and reduces renal clearance by the increased mass. Experimental approach We compared the antithrombotic activities of intact rhodostomin (Rn) and PEGylated rhodostomin (PRn) both in vitro and in vivo systems. In addition, the functional half-life in inhibiting platelet aggregation and the tendency in causing bleeding side effect were investigated. Results Rn and PRn both potently inhibited human and mouse platelet aggregation induced by collagen, thrombin or ADP in vitro with a similar IC50 around 60-100 nM. Rotational thromboelastometry assay indicated that PRn was more effective than Rn in preventing clot formation in human whole blood. In platelet-rich plasma from mice injected with Rn or PRn, the inhibitory effects on collagen-induced platelet aggregation were also comparable, but Rn caused higher bleeding tendency. In ferric chloride-induced arterial thrombosis, Rn and PRn significantly prolonged occlusion time at high dosage (0.2 μg/g). However, PRn obviously prolonged the occlusion time even given at a lower dosage (0.06 μg/g). The functional half-life assay revealed that PEGylation prolonged the in vivo half-life of Rn. Conclusions PRn exhibits higher antithrombotic potency and longer half-life in vivo as compared with native Rn on a molar basis. In addition, PRn exhibits a better safety profile at an efficacious antithrombotic dose in vivo. Therefore, PEGylation may be one of the ideal options in modifying disintegrin derivatives as the safe therapeutic agents for integrin-related diseases.",
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Improved antithrombotic activity and diminished bleeding side effect of a PEGylated αiIbβ3 antagonist, disintegrin. / Hsu, Chun Chieh; Chuang, Woei-Jer; Chung, Ching Hu; Chang, Chien Hsin; Peng, Hui Chin; Huang, Tur Fu.

In: Thrombosis Research, Vol. 143, 01.07.2016, p. 3-10.

Research output: Contribution to journalArticle

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T1 - Improved antithrombotic activity and diminished bleeding side effect of a PEGylated αiIbβ3 antagonist, disintegrin

AU - Hsu, Chun Chieh

AU - Chuang, Woei-Jer

AU - Chung, Ching Hu

AU - Chang, Chien Hsin

AU - Peng, Hui Chin

AU - Huang, Tur Fu

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Introduction The applicability of protein drugs is confined by protein degradation and rapid elimination. PEGylation of polypeptides improves protein stability by sterically obstructing the degradation by serum proteases and reduces renal clearance by the increased mass. Experimental approach We compared the antithrombotic activities of intact rhodostomin (Rn) and PEGylated rhodostomin (PRn) both in vitro and in vivo systems. In addition, the functional half-life in inhibiting platelet aggregation and the tendency in causing bleeding side effect were investigated. Results Rn and PRn both potently inhibited human and mouse platelet aggregation induced by collagen, thrombin or ADP in vitro with a similar IC50 around 60-100 nM. Rotational thromboelastometry assay indicated that PRn was more effective than Rn in preventing clot formation in human whole blood. In platelet-rich plasma from mice injected with Rn or PRn, the inhibitory effects on collagen-induced platelet aggregation were also comparable, but Rn caused higher bleeding tendency. In ferric chloride-induced arterial thrombosis, Rn and PRn significantly prolonged occlusion time at high dosage (0.2 μg/g). However, PRn obviously prolonged the occlusion time even given at a lower dosage (0.06 μg/g). The functional half-life assay revealed that PEGylation prolonged the in vivo half-life of Rn. Conclusions PRn exhibits higher antithrombotic potency and longer half-life in vivo as compared with native Rn on a molar basis. In addition, PRn exhibits a better safety profile at an efficacious antithrombotic dose in vivo. Therefore, PEGylation may be one of the ideal options in modifying disintegrin derivatives as the safe therapeutic agents for integrin-related diseases.

AB - Introduction The applicability of protein drugs is confined by protein degradation and rapid elimination. PEGylation of polypeptides improves protein stability by sterically obstructing the degradation by serum proteases and reduces renal clearance by the increased mass. Experimental approach We compared the antithrombotic activities of intact rhodostomin (Rn) and PEGylated rhodostomin (PRn) both in vitro and in vivo systems. In addition, the functional half-life in inhibiting platelet aggregation and the tendency in causing bleeding side effect were investigated. Results Rn and PRn both potently inhibited human and mouse platelet aggregation induced by collagen, thrombin or ADP in vitro with a similar IC50 around 60-100 nM. Rotational thromboelastometry assay indicated that PRn was more effective than Rn in preventing clot formation in human whole blood. In platelet-rich plasma from mice injected with Rn or PRn, the inhibitory effects on collagen-induced platelet aggregation were also comparable, but Rn caused higher bleeding tendency. In ferric chloride-induced arterial thrombosis, Rn and PRn significantly prolonged occlusion time at high dosage (0.2 μg/g). However, PRn obviously prolonged the occlusion time even given at a lower dosage (0.06 μg/g). The functional half-life assay revealed that PEGylation prolonged the in vivo half-life of Rn. Conclusions PRn exhibits higher antithrombotic potency and longer half-life in vivo as compared with native Rn on a molar basis. In addition, PRn exhibits a better safety profile at an efficacious antithrombotic dose in vivo. Therefore, PEGylation may be one of the ideal options in modifying disintegrin derivatives as the safe therapeutic agents for integrin-related diseases.

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