A Macrocyclic Peptide Library with a Structurally Constrained Cyclopropane‐containing Building Block Leads to Thiol‐independent Inhibitors of Phosphoglycerate Mutase

Here we report the construction of an mRNA‐encoded library of thioether‐closed macrocyclic peptides by using an N ‐chloroacetyl‐cyclopropane‐containing exotic initiator whose structure is more constrained than the ordinary N ‐chloroacetyl‐α‐amino acid initiators. The use of such an initiator has led to a macrocycle library with significantly suppressed population of lariat‐shaped species compared with the conventional libraries. We previously used a conventional library and identified a small lariat thioether‐macrocycle with a tail peptide with a C‐terminal free Cys whose sidechain plays an essential role in potent inhibitory activity against a parasitic model enzyme, phosphoglycerate mutase. On the other hand, the cyclopropane‐containing macrocycle library has yielded a larger thioether‐macrocycle lacking a free Cys residue, which exhibits potent inhibitory activity to the same enzyme with a different mode of action. This result indicates that such a cyclopropane‐containing macrocycle library would allow us to access mechanistically distinct macrocycles.