Bicyclic Peptide Ligands Pulled out of Cysteine-Rich
Peptide Libraries
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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<sub><i>m</i></sub>CX<sub><i>n</i></sub>CX<sub><i>o</i></sub>CX<sub><i>p</i></sub> are oxidized
to connect two pairs of cysteines (C). This allows the generation
of 3 × (<i>m</i> + <i>n</i> + <i>o</i> + <i>p</i>) different peptide topologies because the fourth
cysteine can appear in any of the (<i>m</i> + <i>n</i> + <i>o</i> + <i>p</i>) 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