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.
|State||Published - 8 Feb 2021|
Bibliographical noteFunding 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. ). 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.
© 2021, The Author(s).