A Universal Approach to C-Terminal Thioesters for Protein Synthesis
Principal Investigator: Champak Chatterjee
Native chemical ligation (NCL) is a powerful method for producing protein-based therapeutics and antibiotics. NCL enables total synthesis of full-length proteins by chemoselectively combining two different polypeptide chains, one with a C-terminal peptide thioester and the other with a N-terminal cysteine thiol. Polypeptides bearing the N-terminal Cys may be prepared for NCL by using a protecting group called Fmoc. However, Fmoc chemistry is often incompatible with C-terminal thioesters. Therefore, there is a need for a functional group tolerant, synthetically facile strategy for producing these thioesters to enable this low-cost, flexible method for producing proteins.
Professor Champak Chatterjee and his students have developed a facile and universal approach to synthesis of C-terminal peptide thioesters. Using N-mercaptoethoxyglycinamide (MEGA), they have demonstrated that peptides synthesized with the C-terminal MEGA moiety are readily converted to their thioester form under optimized conditions, and may be directly applied toward NCL. This strategy is compatible with most C-terminal amino acids, including sterically hindered residues. The resulting approach is applicable to inter- and intramolecular one-pot NCL synthesis of proteins, particularly cyclic proteins often used as antibiotics. It is envisioned that this approach will enable production a class of solid phase protein synthesis (SPPS) resins featuring C-terminal amino acids suitable for inexpensive and efficient one-pot protein synthesis.
• Native chemical ligation/protein synthesis
• SPPS resins
• Facile, universally applicable approach to C-terminal thioesters
• Enables inexpensive one-pot NCL reactions, particularly for cyclic peptides
Available for Licensing and Sponsored Research Support
For more info, contact: Forest Bohrer
- Patrick M Shelton, Caroline E Weller, Champak Chatterjee (February 23, 2017), A Facile N-Mercaptoethoxyglycinamide (MEGA) Linker Approach to Peptide Thioesterification and Cyclization, J. Am. Chem. Soc., 3946 - 3949
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