Peptide-containing macrocyclic ligands have shown considerable promise towards modulating challenging biomolecular interactions, which makes them attractive molecular scaffolds as probes and potential pharmacological agents. Here we report a rapid and efficient methodology to afford conformationally constrained Macrocyclic Organo-Peptides Hybrids (MOrPHs) via a tandem chemoselective reaction between a genetically encoded polypeptide and a bifunctional synthetic moiety. This strategy provides the opportunity to exploit both biosynthetic and synthetic combinatorial tools to generate relevant chemical diversity. The presented approach exploits a catalyst-free tandem reaction between a oxyamino/amino-thiol synthetic precursor and a genetically encoded intein fusion protein precursor incorporating a keto group. We will describe how this versatile methodology allows for the creation of diverse macrocycles of variable ring size, architecture, and amino acid composition by exploiting structurally different synthetic precursors as well as by varying the nature of the genetically encoded precursor.

Efficient strategy to afford structurally diverse macrocyclic organo-peptide hybrids (MOrPHs)

244th National Meeting (2012)

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