Lighting the way to larger peptides 

Large peptides and proteins should be more readily accessible thanks to chemists in the US. Katja Michael at the University of Texas at El Paso, and colleagues, has developed a new route to peptide thioesters, crucial intermediates in large peptide synthesis. These thioesters, used to build large peptides by clipped together short ones, have been infamously problematic to make. Michael's new photochemical approach promises much easier access. Michael spoke to OBC about her work:   

Could you briefly explain the focus of your article? 

The structural and functional study of large peptides and proteins is imperative for the understanding of certain diseases and for the potential pharmaceutical intervention with pathogenic processes.   This paper describes a UV-light triggered reaction to connect a peptide with a thiol, creating a peptide thioester. The strength of this method lies in mild and neutral conditions, which avoid notorious side reactions.   

What is your particular interest in this area of research? 

Naturally occurring glycoproteins are difficult to purify due to the existence of different glycoforms. Chemical synthesis may be the best solution to this problem. Native Chemical Ligation (NCL) allows for the synthesis of homogeneous glycoproteins by condensation of structurally well-defined pre-prepared (glyco)peptides and (glyco)peptide-alpha-thioesters.   The synthesis of the latter is not trivial; glycopeptides are assembled by solid phase peptide synthesis (SPPS) using carbohydrate-friendly Fmoc chemistry, but thioesters are not compatible with Fmoc-deprotection conditions due to their base lability.   Our interest lies in developing a convenient synthesis of peptide thioesters, with the goals of constructing the peptide chain by SPPS using Fmoc chemistry, and then releasing the peptide from the solid support and installing the thioester under neutral conditions. These conditions avoid harming potentially present oligosaccharides, the thioester functionality itself, or the chiral integrity of the C-terminal amino acid.   The real advantage of this new development does not lie in the synthesis of peptide thioesters per se, which can be easily prepared by SPPS using the Boc strategy, but in its potential application to acid-sensitive peptide thioesters such as glycopeptide thioesters. 

Where do you see this field developing in the future? Are there any particular challenges? 

We believe that in the future, our photochemical thioesterification will have an impact on glycopeptide thioester synthesis, particularly on the synthesis of glycopeptide thioesters with acid sensitive sialyl and fucosyl residues.   The next challenges in the area of glycoprotein synthesis by NCL will most likely be targeting large glycoproteins, as well as glycoproteins with multiple post-translational modifications.   We believe that our photochemical thioesterification of peptides may help to address these challenges. 

James Mitchell Crow