Journal
CHEMISTRY-AN ASIAN JOURNAL
Volume 15, Issue 17, Pages 2631-2636Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/asia.202000700
Keywords
macrocyclic peptide; mRNA display; genetic code reprogramming; cyclopropane
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Funding
- KAKENHI from the Japan Society for the Promotion of Science (JSPS) [JP 19H01014, 16H06444, JP17H04762, JP18H04382, JP19K22243, JP20H02866]
- Japan Agency for Medical Research and Development (AMED)
- Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research) [JP19am0101090]
- AMED [19ae0101047h0002]
- Takeda Science Foundation
- Inamori Foundation
- intramural program of the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) [1ZIATR000247]
- Grants-in-Aid for Scientific Research [16H06444] Funding Source: KAKEN
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [ZIATR000247] Funding Source: NIH RePORTER
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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.
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