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De Novo Synthetic Design for Ultrafast Formation of Disulfide Bonds in Peptides and Proteins .pdf

submitted on 08.10.2020, 07:17 and posted on 08.10.2020, 09:32 by Shay Laps, Fatima Atamleh, Guy Kamnesky, Hao Sun, ashraf brik

Despite six decades of efforts to synthesize peptides and proteins bearing multiple disulfide bonds, this synthetic challenge remains an unsolved problem in most targets (e.g. knotted mini proteins). Here we show a de novo general synthetic strategy for the ultrafast, high-yielding formation of two and three disulfide bonds in peptides and proteins. We developed an approach based on the combination of a small molecule, UV-light, and palladium for chemo- and regio-selective activation of Cys, which enables the one-pot formation of multiple disulfide bonds in various peptides and proteins. We prepared bioactive targets of high therapeutic potential, including conotoxin, RANTES, EETI-II, and plectasin peptides and the linaclotide drug. We anticipate that this strategy will be a game-changer in preparing millions of inaccessible targets for drug discovery.


This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. [831783]).


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Technion-Israel Institute of Technology



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Declaration of Conflict of Interest

The authors declare no competing interests.