Synthesis of Macrocyclic Organo-peptide Hybrids from Ribosomal Polypeptide Precursors via CuAAC-/Hydrazide-Mediated Cyclization
Macrocyclic peptides have attracted increasing attention as a potential new source of chemical probes and therapeutics. In particular, their conformationally restricted structure combined with a high degree of functional and stereochemical complexity makes them promising scaffolds for targeting biomolecules with high affinity and selectivity. The exploration of this structural class relies on the availability of efficient and versatile methods for the generation of large and diversified libraries of macrocyclic peptide-based molecules. To this end, we have developed a methodology for the synthesis of hybrid organo-peptide macrocycles via the cyclization of ribosomally derived polypeptide sequences with non-peptidic organic linkers. This strategy relies on the chemoselective and bioorthogonal ligation of azide/hydrazide-based “synthetic precursors” with intein-fused polypeptides harboring a side-chain alkyne functionality. This macrocyclization approach was found to proceed with high efficiency across a range of different target peptide sequences spanning 4–12 residues as well as across multiple mono- and diaryl-based synthetic precursors. This versatility combined with the possibility to integrate non-proteinogenic scaffolds into genetically encoded peptide sequences makes this methodology of particularly high value toward the creation and screening of highly diverse libraries of peptide-based macrocycles.
Key wordsMacrocyclic peptide Organo-peptide hybrids Azide–alkyne Huisgen Cycloaddition Click chemistry Intein Intein-mediated ligation Bioorthogonal ligation
This work was supported by the US National Science Foundation grant CHE-1112342 awarded to R.F. J.M.S. is grateful to the NSF Graduate Research Fellowship Program for the financial support. MS instrumentation was supported by the US National Science Foundation grants CHE-0840410 and CHE-0946653.
- 9.Fairlie DP, Tyndall JD, Reid RC, Wong AK, Abbenante G, Scanlon MJ, March DR, Bergman DA, Chai CL, Burkett BA (2000) Conformational selection of inhibitors and substrates by proteolytic enzymes: implications for drug design and polypeptide processing. J Med Chem 43:1271–1281PubMedCrossRefGoogle Scholar