Peptide Thioester and Triazole Derivatives Through On-Resin Dual-Modification of Peptide Thiosulfonates

Modified peptides are an important class of drugs due to their high specificity and affinity in particular to pharmacological targets that are not druggable by conventional small molecules. Methods that allow the efficient diversification of peptides with non-canonical modifications are therefore highly sought after. One possible strategy for accessing broadly diversified peptides is on-resin late-stage modification, whereby a functional site-typically an amino acid side chain or the N-terminus-is usually singly modified after peptide chain assembly, while the other functionalities remain protected. Here, we present an on-resin late-stage dual-modification approach. This approach involves a reaction sequence that includes copper-catalyzed S-alkynylation of a resin-bound peptide thiosulfonate, followed by an iridium-catalyzed azide-alkyne click reaction (IrAAC). Thus, peptides with complex non-canonical modifications are obtained. The dual-modification approach is highly modular and compatible with a wide range of alkynes for S-alkynylation and azides for IrAAC. Furthermore, this chemistry can be used to modify complex peptides, such as the 34-amino-acid WW domain. In a structure-activity relationship study of triazole-containing peptide protease inhibitors of the dengue virus, we demonstrate the great potential of the modular on-resin dual-modification of peptide thiosulfonates for modulating peptide-protein interactions.