Synthesis and evaluation of tripeptidic plasmin inhibitors with nitrile as warhead |
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Authors: | Naoki Teno Tadamune Otsubo Keigo Gohda Keiko Wanaka Takuya Sueda Kiyoshi Ikeda Akiko Hijikata‐Okunomiya Yuko Tsuda |
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Institution: | 1. Hiroshima International University, Faculty of Pharmaceutical Sciences, , Hiroshima, 737‐0112 Japan;2. Computer‐aided Molecular Modeling Research Center, Kansai (CAMM‐Kansai), , Kobe, 653‐0833 Japan;3. Kobe Research Projects on Thrombosis and Haemostasis, , Kobe, 655‐0033 Japan;4. Kobe International University, Faculty of Rehabilitation, , Kobe, 658‐0032 Japan;5. Kobe Gakuin University, Faculty of Pharmaceutical Sciences, , Kobe, 650‐8586 Japan |
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Abstract: | Plasmin is best known as the key molecule in the fibrinolytic system, which is critical for clot lysis and can initiate matrix metalloproteinase (MMP) activation cascade. Along with MMP, plasmin is suggested to be involved in physiological processes that are linked to the risk of carcinoma formation. Plasmin inhibitors could be perceived as a promising new principle in the treatment of diseases triggered by plasmin. On the basis of the peptidic sequence derived from the synthetic plasmin substrate, a series of peptidic plasmin inhibitors possessing nitrile as warhead were prepared and evaluated for their inhibitory activities against plasmin and other serine proteases, plasma kallikrein and urokinase. The most potent peptidic inhibitors with the nitrile warhead exhibit the potency toward plasmin (IC50 = 7.7–11 μM) and are characterized by their selectivity profile against plasma kallikrein and urokinase. The results and molecular modeling of the peptidic inhibitor complexed with plasmin reveal that the P2 residue makes favorable contacts with the open binding pocket comprising the S2 and S3 subsites of plasmin. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd. |
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Keywords: | plasmin inhibitors P2 hydrophobic group nitrile warhead structure– activity relationship |
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