Targeting cancer-specific glycans by cyclic peptide lectinomimics
- 612 Downloads
The transformation from normal to malignant phenotype in human cancers is associated with aberrant cell-surface glycosylation. Thus, targeting glycosylation changes in cancer is likely to provide not only better insight into the roles of carbohydrates in biological systems, but also facilitate the development of new molecular probes for bioanalytical and biomedical applications. In the reported study, we have synthesized lectinomimics based on odorranalectin 1; the smallest lectin-like cyclic peptide isolated from the frog Odorrana grahami skin, and assessed the ability of these peptides to bind specific carbohydrates on molecular and cellular levels. In addition, we have shown that the disulfide bond found in 1 can be replaced with a lactam bridge. However, the orientation of the lactam bridge, peptides 2 and 3, influenced cyclic peptide‘s conformation and thus these peptides’ ability to bind carbohydrates. Naturally occurring 1 and its analog 3 that adopt similar conformation in water bind preferentially l-fucose, and to a lesser degree d-galactose and N-acetyl-d-galactosamine, typically found within the mucin O-glycan core structures. In cell-based assays, peptides 1 and 3 showed a similar binding profile to Aleuria aurantia lectin and these two peptides inhibited the migration of metastatic breast cancer cell lines in a Transwell assay. Altogether, the reported data demonstrate the feasibility of designing lectinomimics based on cyclic peptides.
KeywordsCyclic peptide Lectinomimics Carbohydrate-binding protein Glycosylation Tumor metastasis Cell migration
Aleuria aurantia lectin
Bovine serum albumin
Coefficient of variation
Isothermal titration calorimetry
Matrix assisted laser desorption/ionization time-of-flight
Reverse-phase high pressure liquid chromatography
Sambucus nigra lectin
Ulex europaeus I lectin
Solid-phase peptide synthesis
Trifluoroacetic acid, UV–Vis, ultraviolet–visible
We thank Dr. Anna Knapinska for providing tissue-culture expertise and Ms. Karen Gottwald for editing of the manuscript. This work was partly supported by the Florida Atlantic University [start-up funds to M.C.]; and the National Institutes of Health [National Institute on Drug Abuse (NIDA) RDA039722A to P.C. and National Cancer Institute (NCI) CA178754 to M.C.]. K.M.M. thanks Instituto de Química, UNAM for financing support.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest with the contents of this article.
Research involving human participants and/or animals
This article does not contain any studies with human participants or animals performed by any other authors.
- Dennington R, Keith T, Millam J (2009) Gauss View, version 5, Semichem Inc., Shawnee MissionGoogle Scholar
- Fiedler W, DeDosso S, Cresta S, Weidmann J, Tessari A, Salzberg M, Dietrich B, Baumeister H, Goletz S, Gianni L, Sessa C (2016) A phase I study of PankoMab-GEX, a humanised glyco-optimised monoclonal antibody to a novel tumour-specific MUC1 glycopeptide epitope in patients with advanced carcinomas. Eur J Cancer 63:55–63CrossRefPubMedGoogle Scholar
- Frisch M, Trucks G, Schlegel H, Scuseria G, Robb M, Cheeseman J, Scalmani G, Barone V, Mennucci B, Petersson G (2009) Gaussian 09. Gaussian Inc, Wallingford, p 4Google Scholar
- Häuselmann I, Borsig L (2014) Altered tumor-cell glycosylation promotes metastasis. Front Oncol 4(28):1–15Google Scholar
- McDonald DM, Byrne SN, Payne RJ (2015) Synthetic self-adjuvanting glycopeptide cancer vaccines. Front Chem 3(60):1–8Google Scholar