Macrocyclic Protease Inhibitors with Reduced Peptide Character
| Autor: | Andrew D. Abell, Hon Y. Chan, John B. Bruning, Markus Pietsch, Krystle C. H. Chua, Stephanie Hautmann, Michael Gütschow, Xiaozhou Zhang |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular chemistry.chemical_classification Proteases Binding Sites Protease Chymotrypsin biology Stereochemistry Peptidomimetic medicine.medical_treatment Molecular Conformation Active site Peptide General Chemistry Catalysis Amino acid chemistry biology.protein medicine Protease Inhibitors Peptidomimetics Peptides Protein secondary structure Protein Binding |
| Zdroj: | Angewandte Chemie International Edition. 53:7828-7831 |
| ISSN: | 1433-7851 |
| DOI: | 10.1002/anie.201404301 |
| Popis: | There is a real need for simple structures that define a β-strand conformation, a secondary structure that is central to peptide-protein interactions. For example, protease substrates and inhibitors almost universally adopt this geometry on active site binding. A planar pyrrole is used to replace two amino acids of a peptide backbone to generate a simple macrocycle that retains the required geometry for active site binding. The resulting β-strand templates have reduced peptide character and provide potent protease inhibitors with the attachment of an appropriate amino aldehyde to the C-terminus. Picomolar inhibitors of cathepsin L and S are reported and the mode of binding of one example to the model protease chymotrypsin is defined by X-ray crystallography. |
| Databáze: | OpenAIRE |
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