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Amino Acids

, Volume 49, Issue 11, pp 1867–1883 | Cite as

Targeting cancer-specific glycans by cyclic peptide lectinomimics

  • Maria C. Rodriguez
  • Austin B. Yongye
  • Mihael Cudic
  • Karina Martinez Mayorga
  • Enbo Liu
  • Barbara M. Mueller
  • Jon Ainsley
  • Tatyana Karabencheva-Christova
  • Christo Z. Christov
  • Mare CudicEmail author
  • Predrag CudicEmail author
Original Article

Abstract

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.

Keywords

Cyclic peptide Lectinomimics Carbohydrate-binding protein Glycosylation Tumor metastasis Cell migration 

Abbreviations

RMSD

Root-mean-square deviation

AAL

Aleuria aurantia lectin

ASF

Asialofetuin

BME

β-Mercaptoethanol

Boc

Tert-butyloxycarbonyl

BSA

Bovine serum albumin

CM

Conditioned medium

CV

Coefficient of variation

DIC

Diisopropylcarbodiimide

DMF

N,N-Dimethylformamide

DMSO

Dimethyl sulfoxide

FAM

Fluorescein

FITC

Fluorescein isothiocyanate

Fmoc

Fluorenylmethyloxycarbonyl

HOBt

Hydroxybenzotriazole

ITC

Isothermal titration calorimetry

MALDI–TOF

Matrix assisted laser desorption/ionization time-of-flight

NMM

N-Methylmorpholine

PyBOP

Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate

RP-HPLC

Reverse-phase high pressure liquid chromatography

RT

Room temperature

S/B

Signal-to-background

SNA

Sambucus nigra lectin

UEA-I

Ulex europaeus I lectin

SPPS

Solid-phase peptide synthesis

TFA

Trifluoroacetic acid, UV–Vis, ultraviolet–visible

Notes

Acknowledgements

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.

Supplementary material

726_2017_2485_MOESM1_ESM.pdf (1.2 mb)
Supplementary material 1 (PDF 1248 kb)

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Copyright information

© Springer-Verlag GmbH Austria 2017

Authors and Affiliations

  • Maria C. Rodriguez
    • 1
  • Austin B. Yongye
    • 2
  • Mihael Cudic
    • 2
  • Karina Martinez Mayorga
    • 2
    • 3
  • Enbo Liu
    • 4
  • Barbara M. Mueller
    • 4
  • Jon Ainsley
    • 5
  • Tatyana Karabencheva-Christova
    • 6
  • Christo Z. Christov
    • 6
  • Mare Cudic
    • 1
    Email author
  • Predrag Cudic
    • 1
    Email author
  1. 1.Department of Chemistry and Biochemistry, Charles E. Schmidt College of ScienceFlorida Atlantic UniversityBoca RatonUSA
  2. 2.Torrey Pines Institute for Molecular StudiesPort Saint LucieUSA
  3. 3.Instituto de QuimicaUniversidad Nacional Autónoma de MéxicoMexicoMexico
  4. 4.San Diego Biomedical Research InstituteSan DiegoUSA
  5. 5.University of Northumbria at NewcastleNewcastle upon TyneUK
  6. 6.Michigan Technological UniversityHoughtonUSA

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