biostudies-literatureJbara MNIGMS NIH HHS3154https://www.ebi.ac.uk/biostudies/studies/S-EPMC6082840biostudies-literatureUnknown9(1)Organic chemistry allows for the modification and chemical preparation of protein analogues for various studies. The thiolate side chain of the Cys residue has been a key functionality in these ventures. In order to generate complex molecular targets, there is a particular need to incorporate orthogonal protecting groups of the thiolated amino acids to control the directionality of synthesis and modification site. Here, we demonstrate the tuning of palladium chemoselectivity in aqueous medium for on-demand deprotection of several Cys-protecting groups that are useful in protein synthesis and modification. These tools allow the preparation of highly complex analogues as we demonstrate in the synthesis of the copper storage protein and selectively modified peptides with multiple Cys residuesNature communicationsPalladium prompted on-demand cysteine chemistry for the synthesis of challenging and uniquely modified proteins.PMC6082840R01 GM095822Laps SJbara MMann GBrik AWolberger CKamnesky GMorgan MfalsePalladium prompted on-demand cysteine chemistry for the synthesis of challenging and uniquely modified proteins.Organic chemistry allows for the modification and chemical preparation of protein analogues for various studies. The thiolate side chain of the Cys residue has been a key functionality in these ventures. In order to generate complex molecular targets, there is a particular need to incorporate orthogonal protecting groups of the thiolated amino acids to control the directionality of synthesis and modification site. Here, we demonstrate the tuning of palladium chemoselectivity in aqueous medium for on-demand deprotection of several Cys-protecting groups that are useful in protein synthesis and modification. These tools allow the preparation of highly complex analogues as we demonstrate in the synthesis of the copper storage protein and selectively modified peptides with multiple Cys residues2018-01-01T00:00:00Z2018 Aug2025-04-19T17:54:45.15Z2019-03-26T23:50:58ZS-EPMC60828403008978310.1038/s41467-018-05628-0