5VK0

Dithiocarbamate-inspired side chain stapling chemistry for peptide drug design.

(2019) Chem Sci 10: 1522-1530

• PubMed: 30809370 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1039/c8sc03275k
• Primary Citation of Related Structures:  
  5VK0, 5VK1


• PubMed Abstract: 
  

  Two major pharmacological hurdles severely limit the widespread use of small peptides as therapeutics: poor proteolytic stability and membrane permeability. Importantly, low aqueous solubility also impedes the development of peptides for clinical use. Various elaborate side chain stapling chemistries have been developed for α-helical peptides to circumvent this problem, with considerable success in spite of inevitable limitations. Here we report a novel peptide stapling strategy based on the dithiocarbamate chemistry linking the side chains of residues Lys( i ) and Cys( i + 4) of unprotected peptides and apply it to a series of dodecameric peptide antagonists of the p53-inhibitory oncogenic proteins MDM2 and MDMX. Crystallographic studies of peptide-MDM2/MDMX complexes structurally validated the chemoselectivity of the dithiocarbamate staple bridging Lys and Cys at ( i , i + 4) positions. One dithiocarbamate-stapled PMI derivative, ^DTC PMI, showed a 50-fold stronger binding to MDM2 and MDMX than its linear counterpart. Importantly, in contrast to PMI and its linear derivatives, the ^DTC PMI peptide actively traversed the cell membrane and killed HCT116 tumor cells in vitro by activating the tumor suppressor protein p53. Compared with other known stapling techniques, our solution-based DTC stapling chemistry is simple, cost-effective, regio-specific and environmentally friendly, promising an important new tool for the development of peptide therapeutics with improved pharmacological properties including aqueous solubility, proteolytic stability and membrane permeability.

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Organizational Affiliation: 

School of Pharmacy , Second Military Medical University , Shanghai 200433 , China.