Department of Chemistry Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo, 113-0033, Japan.
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
Chem Asian J. 2020 Sep 1;15(17):2631-2636. doi: 10.1002/asia.202000700. Epub 2020 Aug 11.
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.
在这里,我们报告了一种通过使用含有 N-氯乙酰基-环丙烷的外生引发剂构建硫醚封闭的大环肽的 mRNA 编码文库,该引发剂的结构比普通的 N-氯乙酰基-α-氨基酸引发剂更受限制。使用这种引发剂导致大环肽文库中环化的套索状物质的比例明显降低,与传统文库相比。我们之前使用了一个传统的文库,并鉴定了一个带有尾肽的小套索硫醚大环,其 C 末端有一个游离的半胱氨酸,其侧链在对寄生虫模型酶磷酸甘油酸变位酶的强烈抑制活性中起着至关重要的作用。另一方面,含有环丙烷的大环肽文库产生了一个没有游离半胱氨酸残基的较大的硫醚大环,它对相同的酶具有不同的作用模式,表现出强烈的抑制活性。这一结果表明,这种含有环丙烷的大环肽文库将使我们能够获得具有不同作用机制的大环肽。