Gold(I)-Mediated Depropargylation or Cleavage of Propargyl Modified Peptide Bond in Fully Aqueous Conditions

Since the invention of solid-phase peptide synthesis (SPPS), the revolutionary concept has been going through significant development on different fronts to increase the efficiency of synthesis and enable the synthesis of uniquely modified peptides for various applications. However, researchers frequently encounter so-called difficult sequences such as peptides derived from membrane proteins and β-amyloid peptides, which are either difficult to synthesize or to handle. One of the approaches for overcoming this issue is by interrupting intramolecular or intermolecular hydrogen bonding in peptide or protein secondary structures, which can be done by masking or modifying the amide bond.

Herein we report on utilizing the propargyl group for backbone N-modification at diverse XX-Gly junctions, which is removed on demand by treatment with Gold (I) under fully aqueous media under mild conditions. The straightforward conditions for both installation and removal of this group, provides access to the benefits of backbone N-alkylation, while allowing for on-demand full recovery of the native amide bond by depropargylation. The propargylic backbone N-modification was applied in the total solid-phase chemical synthesis of NEED8 protein without the use of special synthetic analogs such as pseudoproline dipeptide analogs. In addition, the reported approach found to be useful in decaging a broad range of propargyl based protecting groups used in chemical protein synthesis. Remarkably, alternating propargyl site resulted in amide bond cleavage within a few minutes, which extended the applicability of this approach beyond removable backbone modification to a cleavable linker. The easy attach/detach of this functionality was also examined in the loading and releasing of biotinylated peptides from streptavidin resin.