Methods for generating diversified molecular libraries are central to the discovery of chemical probes and therapeutic agents to target protein-protein interactions and other relevant biomolecular complexes. We report a versatile methodology for embedding non-proteogenic, synthetic moieties into genetically encoded peptidic frameworks to generate macrocycles with a hybrid organo-peptide backbone. This approach exploits a dual chemoselective reaction between a bifunctional synthetic precursor and an alkyne-containing intein-fusion protein. The resulting macrocycles can be readily diversified by varying the nature of the synthetic precursor and that of the genetically encoded moiety. This method has been applied to produce cyclic and lariat compounds in isolated form or tethered to a protein of interest. Our further interest is in applying this technology toward high through-put screening in the on-going challenge to create and identify novel protein binders.

Assembly of macrocyclic organo-peptide hybrids (MOrPHs) from genetically encoded precursors

243rd National Meeting (2012)

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