Native Chemical Ligation-Photodesulfurisation in Flow     — ASN Events

 Native Chemical Ligation-Photodesulfurisation in Flow     (#119)

Tim Chisholm 1 , Stephen A. Byrne 1 , Daniel Clayton 1 , Luke J Dowman 1 , Jessica Sayers 1 , Richard J. Payne 1
  1. The University of Sydney, Sydney, NSW, Australia

Peptides and proteins are ubiquitous molecules in living systems and generally exhibit exquisite selectivity for their targets, a property that has led to renewed interest in polypeptides as therapeutics. These “biologics” have been reported to have twice the approval rate of small molecule therapeutics and currently make up 10% of approved drugs. As a result of this renaissance in polypeptide-based therapeutics, it is not surprising that attention has turned to the development of methods to efficiently access these biomolecules. While solid phase peptide synthesis (SPPS) represents the most efficient avenue for generating peptides via chemical synthesis, there is a significant limitation on the size of targets that can be produced en bloc. This limitation of SPPS was largely addressed through the development of native chemical ligation (NCL), a transformative technology that enables convergent and chemoselective fusion of unprotected peptide fragments.1 We report here the use of flow chemistry for the ligation-based assembly of polypeptides.2 We will also present the development of a novel photodesulfurisation transformation that, when coupled with flow NCL, enables efficient access to native polypeptides on time scales up to 2 orders of magnitude faster than current batch NCL−desulfurisation methods. The power of the new ligation−photodesulfurisation flow platform is showcased through the rapid synthesis of the 36 residue clinically approved HIV entry inhibitor enfuvirtide and the peptide diagnostic agent somatorelin, the latter on >100 mg scale.

 

(1)      Dawson, P.; Muir, T.; Clark-Lewis, I.; Kent, S. Science. 1994, 266 (5186), 776.

(2)      Chisholm, T. S.; Clayton, D.; Dowman, L. J.; Sayers, J.; Payne, R. J. J. Am. Chem. Soc. 2018, 140 (29), 9020.