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Targeting cancer-specific glycans by cyclic peptide lectinomimics

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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.

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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

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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.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science, Florida Atlantic University, 777 Glades Road, Boca Raton, FL, 33431, USA

    Maria C. Rodriguez, Mare Cudic & Predrag Cudic

  2. Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port Saint Lucie, FL, 34987, USA

    Austin B. Yongye, Mihael Cudic & Karina Martinez Mayorga

  3. Instituto de Quimica, Universidad Nacional Autónoma de México, 04510, Mexico, Mexico

    Karina Martinez Mayorga

  4. San Diego Biomedical Research Institute, 10865 Road to the Cure, San Diego, CA, 92121, USA

    Enbo Liu & Barbara M. Mueller

  5. University of Northumbria at Newcastle, Newcastle upon Tyne, NE1 8ST, UK

    Jon Ainsley

  6. Michigan Technological University, Houghton, MI, 49931, USA

    Tatyana Karabencheva-Christova & Christo Z. Christov

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  1. Maria C. Rodriguez
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  2. Austin B. Yongye
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Correspondence to Mare Cudic or Predrag Cudic.

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Handling Editor: F. Albericio.

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Rodriguez, M.C., Yongye, A.B., Cudic, M. et al. Targeting cancer-specific glycans by cyclic peptide lectinomimics. Amino Acids 49, 1867–1883 (2017). https://doi.org/10.1007/s00726-017-2485-3

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  • DOI: https://doi.org/10.1007/s00726-017-2485-3

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