Oral Presentation 6th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2017

Accelerated protein synthesis via selenium-mediated ligation chemistry (#3)

Jessica Sayers 1 , Nicholas J Mitchell 1 , Sameer Kulkarni 1 , Daniel Clayton 1 , Richard J Payne 1
  1. The University of Sydney, Camperdown, NSW, Australia

Over the past decade there has been a renaissance in the use of large polypeptides and proteins as therapeutic agents meaning that there is significant need for technologies to rapidly and efficiently access these biomolecules. The advent of peptide ligation technologies, based around the native chemical ligation concept, have revolutionized protein science by providing an avenue to access polypeptides and proteins with tailor-made modifications to maximize specificity and activity or to probe biological function (e.g. through incorporation of post-translational modifications, fluorophores and imaging reagents).1 One of the key problems remaining in the field is that often the time required to assemble a particular protein target is unacceptably long. We have recently reported an additive-free ligation technology between peptides bearing selenoamino acids on their N-termini and peptides containing a C-terminal selenoester functionality.2 These reactions proceed at unprecedented reaction rates and can be coupled with in situ deselenization chemistry to afford native polypeptides and proteins.2,3 The power of the methodology will be highlighted in this talk by discussing the use of the new technology in: 1) the one-pot synthesis of enzymes, 2) the rapid generation of a library of post-translationally modified viral proteins that selectively bind inflammatory human chemokines4 and 3) the total synthesis of a library of anti-thrombotic proteins, each of which could be assembled, purified and quantified for a bioassay within a few hours.5

  1. Malins, L. R.; Payne, R. J. Curr. Opin. Chem. Biol. 2014, 22, 70-78
  2. Mitchell, N. J.; Malins, L. R.; Liu, X.; Thompson, R. E.; Chan, B.; Radom, L.; Payne, R. J. J. Am. Chem. Soc. 2015, 137, 14011-14014.
  3. Malins, L. R.; Mitchell, N. J.; McGowan, S.; Payne, R. J. Angew. Chem. Int. Ed. 2015, 54, 12716-12721.
  4. Wang, X.; Sanchez, J.; Stone, M. Payne, R. J. Angew. Chem. Int. Ed. 2017, 56, 8490-8494.
  5. Mitchell, N. J.; Sayers, J.; Kulkarni, S. S.; Clayton, D.; Goldys, A. M.; Ripoll-Rozada, J.; Pereira, P. J. B.; Chan, B.; Radom, L.; Payne, R. J. Chem. 2017, 2(5), 703-715