Ultrafast Biomimetic Oxidative Folding of Cysteine-rich Peptides and Microproteins in Organic Solvents

Antony Kam, Shining Loo, Yibo Qiu, Chuan Fa Liu, James P Tam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


Disulfides in peptides and proteins are essential for maintaining a properly folded structure. Their oxidative folding is invariably performed in an aqueous-buffered solution. However, this process is often slow and can lead to misfolded products. Here, we report a novel concept and strategy that is bio-inspired to mimic protein disulfide isomerase (PDI) by accelerating disulfide exchange rates many thousand-fold. The proposed strategy termed organic oxidative folding is performed entirely under polar aprotic solvents to yield correctly folded microproteins instantaneously without observable misfolded or dead-end products. Compared to conventional aqueous oxidative folding strategies, enormously large rate accelerations up to 113,200-fold were observed. The feasibility and generality of the organic oxidative folding strategy was successfully demonstrated on 15 cysteine-rich microproteins of different hydrophobicity, lengths (14 to 58 residues), and numbers of disulfides (2 to 5 disulfides), producing the native products in a second and in high yield.
Original languageEnglish
Article numbere202317789
JournalAngewandte Chemie - International Edition
Issue number14
Publication statusPublished - 2 Apr 2024


  • cysteine-rich peptides
  • microproteins
  • organic solvents
  • oxidative folding
  • thiol-disulfide exchange


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