AI Article Synopsis
- Peptides can be used as potential therapeutics for targeting hard-to-drug interactions, but they often face issues like lack of structure and quick breakdown in cells.
- Stapling peptides can stabilize their helical structure and improve their resistance to degradation, but most research has focused on certain spacing patterns of amino acids, leaving the i, i + 3 spacing underexplored.
- This study evaluated different linkers for stapling i, i + 3 residues, finding that this method significantly increases the peptides' resistance to proteolysis compared to other methods, thus enhancing the utility of peptide stapling.
Article Abstract
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.
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| http://dx.doi.org/10.1016/j.bmc.2017.10.037 | DOI Listing |
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