Palladium‐Mediated Direct Disulfide Bond Formation in Proteins Containing S‐Acetamidomethyl‐cysteine under Aqueous Conditions. Issue 17 (20th March 2019)

• Record Type: Journal Article
• Authors: Laps, Shay; Sun, Hao; Kamnesky, Guy; Brik, Ashraf
• Is Part Of: Angewandte Chemie international edition. Volume 58:Issue 17(2019)
• Page Start: 5729
• Page End: 5733
• Publication Date: 2019-03-20
• Subjects: desulfurization -- disulfide bonds -- palladium -- protein synthesis -- S-acetamidomethyl-cysteine; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201900988
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: One of the applied synthetic strategies for correct disulfide bond formation relies on the use of orthogonal Cys protecting groups. This approach requires purification before and after the deprotection steps, which prolongs the entire synthetic process and lowers the yield of the reaction. A major challenge in using this approach is to be able to apply one‐pot synthesis under mild conditions and aqueous media. In this study, we report the development of an approach for rapid disulfide bond formation by employing palladium chemistry and S‐acetamidomethyl‐cysteine [Cys(Acm)]. Oxidation of Cys(Acm) to the corresponding disulfide bond is achieved within minutes in a one‐pot operation by applying palladium and diethyldithiocarbamate. The utility of this reaction was demonstrated by the synthesis of the peptide oxytocin and the first total chemical synthesis of the protein thioredoxin‐1. Our investigation revealed a critical role of the Acm protecting group in the disulfide bond formation, apparently due to the generation of a disulfiram in the reaction pathway, which significantly assists the oxidation step. Abstract : Acm protects and connects : The chemistry of palladium and diethyldithiocarbamate was applied for the efficient and rapid conversion of S‐acetamidomethyl (Acm) protected cysteine into the corresponding disulfide. Disulfiram is suggested to play a key role in this process. This approach enabled the one‐pot synthesis of disulfide bond containing peptides and proteins under mild and fully aqueous conditions.