Peptide-based macrocycles have shown promise as probes and pharmaceutical agents from their ability to modulate naturally-occurring biological interactions. Here we report an efficient method for the rapid generation of conformationally constrained Macrocyclic Organo-Peptide Hybrids (MOrPHs) through two orthogonal, chemoselective reactions between a genetically encoded intein fusion protein (with a non-natural amino acid containing a keto side-chain) and a bifunctional synthetic molecule (with an oxyamino and amino-thiol functionality) that enables cyclization. Modular manipulation of the genetically encoded polypeptides and the use of structurally diverse synthetic precursors allows for the creation of diverse macrocycles of variable ring size, architecture, and amino acid composition, all in a catalyst-free reaction.

Efficient methodology for the rapid generation of structurally diverse Macrocyclic Organo-Peptide Hybrids (MOrPHs)

245th National Meeting (2013)

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