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 anN-chloroacetyl-cyclopropane-containing exotic initiator whose structure is more constrained than the ordinaryN-chloroacetyl-alpha-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.