Macrocyclization can be used to constrain peptides in their bioactive conformations, thereby supporting target affinity and bioactivity. In particular, for the targeting of challenging protein–protein interactions, macrocyclic peptides have proven to be very useful. Available approaches focus on the stabilization of α‐helices, which limits their general applicability. Here we report for the first time on the use of ring‐closing alkyne metathesis for the stabilization of an irregular peptide secondary structure. A small library of alkyne‐crosslinked peptides provided a number of derivatives with improved target affinity relative to the linear parent peptide. In addition, we report the crystal structure of the highest‐affinity derivative in a complex with its protein target 14‐3‐3ζ. It can be expected that the alkyne‐based macrocyclization of irregular binding epitopes should give rise to new scaffolds suitable for targeting of currently intractable proteins.
Macrocyclic
peptides can interfere with challenging biomolecular
targets including protein–protein interactions. Whereas there
are various approaches that facilitate the identification of peptide-derived
ligands, their evolution into higher affinity binders remains a major
hurdle. We report a virtual screen based on molecular docking that
allows the affinity maturation of macrocyclic peptides taking non-natural
amino acids into consideration. These macrocycles bear large and flexible
substituents that usually complicate the use of docking approaches.
A virtual library containing more than 1400 structures was screened
against the target focusing on docking poses with the core structure
resembling a known bioactive conformation. Based on this screen, a
macrocyclic peptide 22 involving two non-natural amino
acids was evolved showing increased target affinity and biological
activity. Predicted binding modes were verified by X-ray crystallography.
The presented workflow allows the screening of large macrocyclic peptides
with diverse modifications thereby expanding the accessible chemical
space and reducing synthetic efforts.
A combination of free energy perturbations and molecular dynamics simulations were applied to investigate large macrocyclic ligands and their receptor binding.
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