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A Macrocyclic Peptide Library with a Structurally Constrained Cyclopropane‐containing Building Block Leads to Thiol‐independent Inhibitors of Phosphoglycerate Mutase
Author(s) -
Okuma Rika,
Kuwahara Tomoki,
Yoshikane Takafumi,
Watanabe Mizuki,
Dranchak Patricia,
Inglese James,
Shuto Satoshi,
Goto Yuki,
Suga Hiroaki
Publication year - 2020
Publication title -
chemistry – an asian journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.18
H-Index - 106
eISSN - 1861-471X
pISSN - 1861-4728
DOI - 10.1002/asia.202000700
Subject(s) - phosphoglycerate mutase , cyclopropane , thiol , block (permutation group theory) , chemistry , biochemistry , combinatorial chemistry , enzyme , organic chemistry , combinatorics , mathematics , glycolysis , ring (chemistry)
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.