A study of 2-component i, i + 3 peptide stapling using thioethers
| Autor: | Lauren E. St. Louis, Marcey L. Waters, Tayliz M. Rodriguez |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Proteases
Clinical Biochemistry Cell Pharmaceutical Science Model system Proteolytic degradation Peptide Sulfides 010402 general chemistry 01 natural sciences Biochemistry Protein Structure Secondary chemistry.chemical_compound Drug Discovery medicine Humans Amino Acid Sequence Bifunctional Molecular Biology chemistry.chemical_classification Protein Stability 010405 organic chemistry Circular Dichroism Organic Chemistry Small molecule Combinatorial chemistry 0104 chemical sciences Cytosol HEK293 Cells medicine.anatomical_structure chemistry Molecular Medicine Peptides |
| Zdroj: | Bioorganic & Medicinal Chemistry. 26:1203-1205 |
| ISSN: | 0968-0896 |
| Popis: | Peptides are promising scaffolds for use as therapeutics, targeting interactions previously considered to be “undruggable” by small molecules. While short peptides are generally unstructured in solution and rapidly degraded by proteases in the cell cytosol, peptide stapling offers an effective method to both stabilize peptides in a helical structure and increase resistance to proteolytic degradation. Most studies of peptide stapling have focused on residues with i, i + 4 and i, i + 7 spacing, while stapling of residues with i, i + 3 spacing has been understudied. Herein, we evaluated a suite of bifunctional linkers for stapling between residues with i, i + 3 spacing, comparing the ability of each compound to react with the peptide and the degree of helicity conferred. Finally, we evaluated the ability of the stapling to increase proteolytic resistance in cell lysates, comparing stapling of i, i + 3 and i, i + 4 spacing, with i, i + 3 spacing resulting in a greater increase in peptide half-life in the model system. This presents an effective stapling strategy, adding to the peptide stapling toolbox. |
| Databáze: | OpenAIRE |
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