New Bivalent Thrombin Inhibitors with N? (Methyl)Arginine at the P1-Position
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Torsten Steinmetzer
Abstract
A series of bivalent thrombin inhibitors was synthesized, consisting of a dphenylalanylprolylN?(methyl) arginyl active site blocking segment, a fibrinogen recognition exosite inhibitor part, and a peptidic linker connecting these fragments. The methylation of the P1 amino acid led to a moderate decrease in affinity compared with the unmethylated analog. In addition, it prevented the thrombin catalyzed proteolysis, independent of the P1' amino acid used. This is a significant advantage compared to the original hirulogs, which strictly require a proline as P1' amino acid to reduce the cleavage Cterminal to the arginyl residue. Several analogs were prepared by incorporation of different P1' amino acids found in natural thrombin substrates. The most potent inhibitor was I-11 [dCha ProN(Me)ArgThr(Gly)[5]DYEPIPEEAChadGlu] with a K of 37 pM. I-11 is highly selective and no inhibition of the related serine proteases trypsin, factor Xa and plasmin was observed. The stability of I-11 in human plasma in vitro was strongly improved compared to hirulog-1. In addition, a significantly reduced plasma clearance of I-11 was observed after intravenous injection in rats. Results from molecular modeling suggest that a strong reorganization of the hydrogen bonds in the active site of thrombin may result in the proteolytic stability found in this inhibitor series.
Copyright © 2000 by Walter de Gruyter GmbH & Co. KG
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Artikel in diesem Heft
- Characterization of Regulatory Elements in the 5'-Flanking Region of the GM2 Activator Gene
- Transcriptional Activity of GLI1 Is Negatively Regulated by Protein Kinase A
- Peptide Bond Synthesis: Function of the efp Gene Product
- Molecular Cloning, Expression and Purification of Muscle Fructose-1,6-Bisphosphatase from Zaocys dhumnades: the Role of the N-Terminal Sequence in AMP Activation at Alkaline pH
- The pH-Dependent Interaction of Cinnamomin with Lipid Membranes Investigated by Fluorescence Methods
- Nitric Oxide Detection and Visualization in Biological Systems. Applications of the FNOCT Method
- Processing of V-ATPase Subunit B of Mesembryanthemum crystallinum L. Is Mediated in Vitro by a Protease and/or Reactive Oxygen Species
- The Thioredoxin Boxes of Thyroglobulin: Possible Implications for Intermolecular Disulfide Bond Formation in the Follicle Lumen
- New Bivalent Thrombin Inhibitors with N? (Methyl)Arginine at the P1-Position
- Multiple Promoters Direct the Tissue-Specific Expression of Rat Mitochondrial Glycerol-3-Phosphate Dehydrogenase
- Characterization of SNP, a Novel Tissue- and Phase-Specific Nuclear Protein Expressed during the Proliferative Phase in the Oviduct of the Lizard Podarcis sicula Raf.
- Association of Betaine-Homocysteine S-Methyltransferase with Microtubules
- Re-Evaluation of Amino Acid Sequence and Structural Consensus Rules for Cysteine-Nitric Oxide Reactivity
- Expression of Human Tissue Kallikrein in Differentiated HL-60 Cells
- Erratum
