Anticoagulant Peptides; Synthesis, Stability and Antithrombin Activity of Hirudin C-Terminal-Related Peptides and Their Disulfated Analog

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概要

• 論文の詳細を見る

• We designed a unique anticoagulant decapeptide, which possesses two O-sulfated tyrosine residues, based on the structure of hirudin's C-terminal functional domain. We first prepared a series of octa-, nona- and decapeptides with no sulfation, Suc-Phe-Glu-Pro-Ile-Pro-Glu-Tyr-Tyr-X-OH [X=bond, Leu or Leu-Gln], by a solution phase method and measured their thrombin times (TT) using human thrombin and rabbit plasma. The shortest octapeptide (3a) showed full antithrombin activity compareble to that of the lead compound hirudin (54-65), and the longest decapeptide (3c) prolonged TT most potently with an IC_<50> value of 5.8 μM. We consequently converted 3c to a disulfated decapeptide (NF-22) with SO_3・pyridine complex and compared its antithrombin activity with that of known hirudin-related peptides : hirugen, MDL28050 and hirulog-1. NF-22 showed potent antithrombin activity with an IC_<50> value of 0.3 μM, being more potent than hirugen and MDL28050 (IC_<50> values of 4.0 μM and 1.1 μM, respectively). NF-22 was as potent as hirulog-1. NF-22 showed no change in activity in aqueous solution for 10 d at 60℃, and remained about 90% unchanged in rat plasma on incubation for 24 h at 37℃, whereas the corresponding unsulfated peptide (3c) was completely digested under the same condition. NF-22 appears to be one of the most potent and stable peptide anticoagulants among the hirudin analogs.

• 公益社団法人日本薬学会の論文
• 1996-07-15

著者

• MORIKAWA Tadanori

  Research Institute, Daiichi Fine Chemical Co., Ltd.

• HAYASHI Hideya

  Pharmaceuticals and Biotechnology Laboratory, Japan Energy Corporation

• Hayashi H

  Univ. Tokyo Tokyo Jpn

• Ogawa T

  Kyoto Univ. Kyoto Jpn

• Hayashi H

  Drug Research Division Dainippon Sumitomo Pharma Co. Ltd.

• Hayashi Hideya

  Pharmaceuticals And Biotechnology Laboratory Japan Energy Corporation

• Hayashi H

  Pharmaceuticals & Biotechnology Laboratory Japan Energy Corporation

• Hayashi Hideya

  Pharmaceuticals & Biotechnology Laboratory Japan Energy Corporation

• OKAYAMA Toru

  Research Institute, Daiichi Fine Chemical Co., Ltd.

• HAGIWARA Masaki

  Research Institute, Daiichi Fine Chemical Co., Ltd.

• Morikawa Tadanori

  Research Institute Daiichi Fine Chemical Co. Ltd.

• Ogawa Tadashi

  Graduate School Of Bioagricultural Sciences Nagoya University

• Okayama T

  Research Institute Daiichi Fine Chemical Co. Ltd.

• Okayama Toru

  Research Institute Daiichi Fine Chemical Co. Ltd.

• MURAMATSU Ryo

  Pharmaceuticals and Biotechnology Laboratory, Japan Energy Corporation

• SEKI Sumie

  Research Laboratory, Fuji Chemical Industries, Ltd.,

• NUKUI Eriko

  Research Laboratory, Fuji Chemical Industries, Ltd.,

• Seki Sumie

  Research Laboratory Fuji Chemical Industries Ltd.

• Nukui Eriko

  Research Laboratory Fuji Chemical Industries Ltd.

• Muramatsu R

  Japan Energy Corp. Saitama Jpn

• Muramatsu Ryo

  Pharmaceuticals & Biotechnology Laboratory Japan Energy Corporation

• Hagiwara M

  Research Institute Daiichi Fine Chemical Co. Ltd.

• Hagiwara Masaki

  Research Institute Daiichi Fine Chemical Co. Ltd.

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