De Novo Synthetic Design for Ultrafast Formation of Disulfide Bonds in Peptides and Proteins .pdf
Preprints are manuscripts made publicly available before they have been submitted for formal peer review and publication. They might contain new research findings or data. Preprints can be a draft or final version of an author's research but must not have been accepted for publication at the time of submission.
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.