Design of Inhibitors for Human Tissue Kallikrein Using Non-Natural Aromatic and Basic Amino Acids
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Daniel C. Pimenta
Abstract
We explored the unique substrate specificity of the primary S1 subsite of human urinary kallikrein (hK1), which accepts both Phe or Arg synthesizing and assaying peptides derived from PhenylacetylPheSer ArgEDDnp, a previously described inhibitor with analgesic and antiinflammatory activities [Emim et al., Br. J. Pharmacol. 130 (2000), 1099 1107]. Phe was substituted by amino acids containing larger aliphatic or aromatic side chains as well as by nonnatural basic amino acids, which were designed to combine a large hydrophobic and/or aromatic group with a positivelycharged group at their side chains. In general, all peptides with basic amino acids represented better inhibitors than those with hydrophobic amino acids. Furthermore, the S1 subsite specificity proved to be much more selective than the mere distinction between Phe and Arg, for minor differences in the side chains of the nonnatural amino acids resulted in major differences in the Ki values. Finally, we present a series of peptides that were assayed as competitive inhibitors for human tissue kallikrein that may lead to the development of novel peptides, which are both more potent and selective.
Copyright © 2002 by Walter de Gruyter GmbH & Co. KG
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- Nobuhiko Katunuma: An Outstanding Scientific and Professional Career of a Warm-Hearted Person. Reflections on the Occasion of his 75th Birthday
- Structural and Functional Diversity of Connexin Genes in the Mouse and Human Genome
- Congopain from Trypanosoma congolense: Drug Target and Vaccine Candidate
- Biosynthesis of Lysosomal Proteinases in Health and Disease
- Calpain Function in the Differentiation of Mesenchymal Stem Cells
- Ku Antigen Supports Termination of Mammalian rDNA Replication by Transcription Termination Factor TTF-I
- Thyroid Stimulating Hormone Upregulates Secretion of Cathepsin B from Thyroid Epithelial Cells
- Selective Release of Calpain Produced αII-Spectrin (α-Fodrin) Breakdown Products by Acute Neuronal Cell Death
- Altered Storage of Proteases in Mast Cells from Mice Lacking Heparin: A Possible Role for Heparin Carboxypeptidase A Processing
- Clustering-Induced Signaling of CEACAM1 in PC12 Cells
- Spin Adducts of Superoxide, Alkoxyl, and Lipid-Derived Radicals with EMPO and Its Derivatives
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- Amyloid Fibril Formation by Human Stefin B in vitro: Immunogold Labelling and Comparison to Stefin A
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