Using the MCoTI-II cyclotide scaffold to design a stable cyclic peptide antagonist of SET, a protein overexpressed in human cancer

D'Souza, Charlotte, Henriques, Sonia Troeira, Wang, Conana K., Cheneval, Olivier, Chan, Lai Yue, Bokil, Nilesh J., Sweet, Matthew J. and Craik, David J. (2016) Using the MCoTI-II cyclotide scaffold to design a stable cyclic peptide antagonist of SET, a protein overexpressed in human cancer. Biochemistry, 55 2: 396-405. doi:10.1021/acs.biochem.5b00529


Author D'Souza, Charlotte
Henriques, Sonia Troeira
Wang, Conana K.
Cheneval, Olivier
Chan, Lai Yue
Bokil, Nilesh J.
Sweet, Matthew J.
Craik, David J.
Title Using the MCoTI-II cyclotide scaffold to design a stable cyclic peptide antagonist of SET, a protein overexpressed in human cancer
Journal name Biochemistry   Check publisher's open access policy
ISSN 1520-4995
0006-2960
Publication date 2016-01-19
Sub-type Article (original research)
DOI 10.1021/acs.biochem.5b00529
Open Access Status Not Open Access
Volume 55
Issue 2
Start page 396
End page 405
Total pages 10
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2017
Language eng
Formatted abstract
The SET protein is a promising drug target in cancer therapy, because of its ability to inhibit the function of the tumor suppressor gene protein phosphatase 2A (PP2A). COG peptides, derived from apolipoprotein E (apoE), are potent antagonists of SET; they induce cytotoxicity in cancer cells upon binding to intracellular SET and modulate the nuclear factor kappa B (NF-κB) signaling pathway. However, the therapeutic potential of COG peptides is limited, because of their poor proteolytic stability and low bioavailability. In this study, the COG peptide, COG1410, was stabilized by grafting it onto the ultrastable cyclic peptide scaffold, Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II). The grafted MCoTI-II peptides were cytotoxic to a cancer cell line and showed high stability in human serum. The most potent grafted MCoTI-II peptide inhibited lipopolysaccharide (LPS)-mediated activation of NF-κB in murine macrophages. Overall, this study demonstrates the application of the MCoTI-II scaffold for the development of stable peptide drugs for cancer therapy.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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