AI Article Synopsis
- Bicyclic peptide ligands demonstrate strong binding affinity and target specificity, but their traditional production method is complex and limited to specialized labs.
- A new, simpler method for generating these ligands involves creating combinatorial peptide libraries that can yield a diverse range of bicyclic structures through oxidation to connect cysteines.
- This approach not only simplifies the production process but also produces peptides with strong binding capabilities, confirmed by structural analysis showing the crucial role of disulfide bridges.
Article Abstract
Bicyclic peptide ligands were found to have good binding affinity and target specificity. However, the method applied to generate bicyclic ligands based on phage-peptide alkylation is technically complex and limits its application to specialized laboratories. Herein, we report a method that involves a simpler and more robust procedure that additionally allows screening of structurally more diverse bicyclic peptide libraries. In brief, phage-encoded combinatorial peptide libraries of the format X(m)CX(n)CX(o)CX(p) are oxidized to connect two pairs of cysteines (C). This allows the generation of 3 × (m + n + o + p) different peptide topologies because the fourth cysteine can appear in any of the (m + n + o + p) randomized amino acid positions (X). Panning of such libraries enriched strongly peptides with four cysteines and yielded tight binders to protein targets. X-ray structure analysis revealed an important structural role of the disulfide bridges. In summary, the presented approach offers facile access to bicyclic peptide ligands with good binding affinities.
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| http://dx.doi.org/10.1021/ja400461h | DOI Listing |
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