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

Autor:	Mizuki Watanabe, Patricia Dranchak, Satoshi Shuto, Takafumi Yoshikane, Hiroaki Suga, Rika Okuma, James Inglese, Tomoki Kuwahara, Yuki Goto
Rok vydání:	2020
Předmět:	Cyclopropanes Macrocyclic Compounds Stereochemistry Population Peptide 010402 general chemistry 01 natural sciences Biochemistry Article Cyclopropane Phosphoglycerate mutase Residue (chemistry) chemistry.chemical_compound Peptide Library Animals mRNA display Sulfhydryl Compounds Enzyme Inhibitors Caenorhabditis elegans Mode of action education Phosphoglycerate Mutase chemistry.chemical_classification education.field_of_study Molecular Structure 010405 organic chemistry Organic Chemistry General Chemistry 0104 chemical sciences Enzyme chemistry Peptides
Zdroj:	Chem Asian J
ISSN:	1861-471X 1861-4728
DOI:	10.1002/asia.202000700
Popis:	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.
Databáze:	OpenAIRE
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