Dithiocarbamate-inspired side chain stapling chemistry for peptide drug design

Chemical Science
Xiang LiWuyuan Lu

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, DTCPMI, showed a 50-fold stronger binding to MDM2 and MDMX than its linear counterpart. Importantly, in contrast to PMI and its linear derivatives, the DTCPMI peptide actively traversed the cell membrane and killed HCT116 tumor cells in vitro by activating the tumor suppressor protein p53. Compared with o...Continue Reading

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Citations

Jun 22, 2019·Chemical Communications : Chem Comm·Jiraborrirak CharoenpattarapreedaDavid R Spring
Jan 7, 2021·Chemical Society Reviews·Marzieh AhangarpourMargaret A Brimble
Jul 13, 2020·Journal of Controlled Release : Official Journal of the Controlled Release Society·Wangxiao HeWuyuan Lu
Aug 17, 2020·Chemical Reviews·Xiang LiHong-Gang Hu
Aug 28, 2021·Antibiotics·Mengjun ZhengXiang Li

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Methods Mentioned

BETA
surface plasmon resonance
chip
Circular dichroism
flow cytometry
fluorescence-activated cell sorting
FACS

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