General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins

Shay Laps, Fatima Atamleh, Guy Kamnesky, Hao Sun, Ashraf Brik

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19 Scopus citations


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 develop an approach based on the combination of a small molecule, ultraviolet-light, and palladium for chemo- and regio-selective activation of cysteine, which enables the one-pot formation of multiple disulfide bonds in various peptides and proteins. We prepare 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.

Original languageEnglish
Article number870
Pages (from-to)870
JournalNature Communications
Issue number1
StatePublished - 8 Feb 2021
Externally publishedYes

Bibliographical note

Funding Information:
A.B. holds the Jordan and Irene Tark Academic Chair. 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]). S.L. thanks the Technion for the Jacobs fellowship for excellence. We thank Prof. Michael M. Meijler from the Department of Chemistry, Ben-Gurion University, for his assistance with the plectasin activity assay. We thank Dr. Muhammad Jbara for useful discussion.

Publisher Copyright:
© 2021, The Author(s).


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