Peptide Macrocyclization Guided by Reversible Covalent Templating

Towards sequence/size defined macrocycles: Here we demonstrate a non-nucleic acid templated synthesis of peptide macrocycle complexes. By using hydrazone bonds, we template and organize short peptide oligomers along a solid supported peptide strand and cyclize them using microwave assisted solid phase peptide synthesis to form sequence and size defined macrocycles. The products are then released from the solid support via acidic hydrolysis and detected by LC–MS.

Abstract

The creation of complementary products via templating is a hallmark feature of nucleic acid replication. Outside of nucleic acid-like molecules, the templated synthesis of a hetero-complementary copy is still rare. Herein we describe one cycle of templated synthesis that creates homomeric macrocyclic peptides guided by linear instructing strands. This strategy utilizes hydrazone formation to pre-organize peptide oligomeric monomers along the template on a solid support resin, and microwave-assisted peptide synthesis to couple monomers and cyclize the strands. With a flexible templating strand, we can alter the size of the complementary macrocycle products by increasing the length and number of the binding peptide oligomers, showing the potential to precisely tune the size of macrocyclic products. For the smaller macrocyclic peptides, the products can be released via hydrolysis and characterized by ESI-MS.

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