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

ABSTRACT: 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.

SUBMITTER: Laps S

PROVIDER: S-EPMC7870662 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Laps Shay S Atamleh Fatima F Kamnesky Guy G Sun Hao H Brik Ashraf A

Nature communications 20210208 1

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 ...[more]

PMID: 33558523

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