ELITE NETZWERK BAYERN

English  Sprachen Icon  |  Gebärdensprache  |  Leichte Sprache  |  Kontakt


Forschungsarbeit

Galectin-1: Sweet prospects for cancer research

By Nadja Bertleff (11.07.2013)

The World Health Organization (WHO) states on its homepage that cancer, a leading factor for death worldwide, accounted for 7.6 million deaths in 2008. Prognoses indicate that the number will rise continuously and reach more than 13 million in 2030. In the last years preventive steps, early detection and medical treatment, such as surgery and chemotherapy, have intervened successfully in the progress of the disease. However, there is still a huge lack of side-effect free therapies and reliable screening methods for a number of cancer types. Consequently, contributions to this research area are of eminent social and scientific importance.

Thus, a regulation of galectin-1 promises effective preventive and therapeutic possibilities. The natural binding motif N-Acetyllactosamine shows only weak binding affinity with a binding constant of 100 M and can therefore not fulfil this job. The development of high affine ligands is the key for regulating pathological processes of galectin-1 and a possible way to explore cellular mechanisms. In my PhD thesis I chose a rational, highly interdisciplinary approach for the design and the synthesis of strong and selective binding partners. Final drug molecules will thereby exploit the inherent affinity of N-Acetyllactosamine while additional synthetic modifications address amino acids adjacent to the CRD. To realise this intent I first produced the target human galectin-1 by overexpression in E.coli. Crystallisation experiments and structure elucidation gave a comprehensive idea of the protein’s three-dimensional constitution. Subsequent docking studies with the X-ray structure of galectin-1 and “reactive” N-Acetyllactosamine candidates represented an important intermediate goal in the rational ligand development. 

[Bildunterschrift / Subline]: Fig. 1: A) X-ray structure of human galectin-1 in complex with N-Acetyllactosamine (LacNAc) (unpublished data, in cooperation with Dr. C. Grimm, Biocenter University of Würzburg). B) Scheme of human cell surface. Galectin-1 binds terminal LacNAc of glycoproteins and –lipids. Signal transductions are introduced and networks formed.

In this context, the protein galectin-1 has gained increasing interest and proposed to be an attractive pharmaceutical target.[1] The polypeptide is overexpressed in malignant tissues and involved in numerous types of cancer.[2] Clinically, galectin-1 is a promising tumor marker as the exceeding of a certain threshold concentration indicates in all probability tumor cells.[3] Recently, indications have confirmed that galectin-1 is involved in a wider physiological context.[4] Due to the participation in many inter- and intracellular processes the protein has advanced to a key-player in signal transduction. However, most interactions on cellular level still need to be decoded and the study of structure recognition events promises to shed light on those processes. 

A closer look at the prominent member of carbohydrate binding lectins reveals a homodimeric structure (Fig. 1A). Characteristic carbohydrate recognition domains (CRD) on opposite sites of the dimer interact selectively with -galactosides (like lactose and N-Acetyllactosamine) and lead to multivalent networks. Cell surfaces present those binding partners of galectin-1 as they are decorated by complex carbohydrate structures of membrane-anchored glycopeptides and –lipids (Fig. 1B). Interactions between the protein and glycoconjugates of the cell surface introduce biomolecular processes like cell growth, migration, immune reactions and account for apoptosis of T helper cells and tumor progression.[4-6]

Thus, a regulation of galectin-1 promises effective preventive and therapeutic possibilities. The natural binding motif N-Acetyllactosamine shows only weak binding affinity with a binding constant of 100 M and can therefore not fulfil this job. The development of high affine ligands is the key for regulating pathological processes of galectin-1 and a possible way to explore cellular mechanisms. In my PhD thesis I chose a rational, highly interdisciplinary approach for the design and the synthesis of strong and selective binding partners. Final drug molecules will thereby exploit the inherent affinity of N-Acetyllactosamine while additional synthetic modifications address amino acids adjacent to the CRD. To realise this intent I first produced the target human galectin-1 by overexpression in E.coli. Crystallisation experiments and structure elucidation gave a comprehensive idea of the protein’s three-dimensional constitution. Subsequent docking studies with the X-ray structure of galectin-1 and “reactive” N-Acetyllactosamine candidates represented an important intermediate goal in the rational ligand development. 

Organic synthesis of promising carbohydrate precursors and cocrystallisation with galectin-1 confirmed the computational drug-design. Intense investigation of the protein surface led to promising modifications that were introduced into the “reactive” carbohydrate precursor via one-step syntheses. First candidates from molecular-guided drug design are currently under investigation and first results of surface plasmon resonance (SPR) binding assays will be shown in the talk. Further ongoing cocrystallisation experiments intend to elucidate the binding mode of novel, high affine galectin-1 ligands. 

Literature:

[1] Smetana Jr, K; André, S.; Kaltner, H.; Kopitz, J.; Gabius, H.-J. Expert Opin. Ther. Targets, 2013, 17, 379-392.
[2] Rabinovich, G. A. Br. J. Cancer 2005, 92, 1188.
[3] Demydenko, D.; Berest, I. Experimental Oncology 2009, 31, 74.
[4] Camby, I.; Le Mercier, M.; Lefranc, F.; Kiss, R. Glycobiology 2006, 16, 137R.
[5] Perillo, N. L.; Pace, K. E.; Seilhamer, J. J.; Baum, L. G. Nature 1995, 378, 736.
[6] Rabinovich, G. A.; Toscano, M. A. Nat. Rev. Immunol. 2009, 9, 338.


Scientific career
  • 2004-2009
  • University education in chemistry (Diplom), Julius-Maximilians-Universität Würzburg,
  • 2009
  • Diploma thesis in the group of Prof. Dr. T. Brixner, Institute for Physical Chemistry, University of Würzburg

Awards and Scholarships
  • 2007-2010
  • Max Weber-Program of the state of Bavaria
  • 2007 & 2010
  • Award of the faculty for Chemistry and Pharmacy for excellent results in the Diploma and intermediate exams, University of Würzburg
  • 2010-2012
  • Scholarship by Fonds der Chemischen Industrie

Publication
  • * Seibel, J.; König, S.; Göhler, A.; Memmel, E.; Bertleff, N.; Sauer, M. Expert Rev. Proteomics 2013, 10, 25.