Lybatide: Naturally‐Occurring Disulfide‐Stapled Helical Peptides from Lycium barbarum

Small molecules and proteins represent the two major groups of compounds that are currently approved for human use. In between the molecular size of these two groups are the constrained peptides, a class of compounds that integrate their drug‐like advantages. Constrained peptides share the advantage of proteins for high on‐target specificity and low off‐target adverse side effects. They also have the robustness of small molecules to tolerate thermal, chemical and enzymatic degradation. Currently, naturally‐occurring constrained peptides in plants is an underexplored chemical space for drug discovery. Here we report the discovery and characterization of Lybatides, a constrained peptides with unusual cysteine motif and disulfide connectivity from the root bark of Lycium babarum , the plant that produces the popular functional food and herb, wolfberries. Importantly, an X‐ray crystallographic study revealed the presence of a helix as a dominant feature in the lybatide structure, which is stabilized by four cystine bonds. The presence of a single helix without stabilization by another helix or β‐strand is most unusual and has not been reported. As such, the lybatide structure resembles a naturally‐occurring stapled helical peptide. Lybatides are non‐cytotoxic, up to 100 μM, to the cell lines tested and are stable against thermal, acidic and proteolytic denaturation for up to 2 hours. The presence of the helix in the lybatide scaffold should allow the grafting of helical bioactive peptides for developing peptidyl therapeutics. Overall, this study provides a new scaffold and expands the number of existing constrained peptide scaffolds for drug design. Support or Funding Information This research was supported by a Competitive Research Grant from the National Research Foundation in Singapore (NRF‐CRP8‐2011‐05) and an NTU iFood Research Grant (M4081467.080).