High-affinity lectins from pathogens: the potential targets for antiadhesive drug design

O. Šulák¹, L. Malinovská¹, G. Cioci², J. Houser¹, N. Kostlánová¹, E. Lameignere³, M. Pokorná¹, A. Imberty³, M. Wimmerová^1,4

¹National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic

²European Synchrotron Radiation Facility, 6 rue Jules Horowitz, 38043 Grenoble, France

³Molecular Glycobiology, CERMAV-CNRS, BP53, 38041 Grenoble Cedex 9, France

⁴Department of Biochemistry, Faculty of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic

michaw@chemi.muni.cz

Protein-carbohydrate interactions play an important role in many biologically relevant processes including differentiation, signalling, fertilisation as well as cancerogenesis or metastasis development. Glycoproteins on cell surfaces are important for communication between cells, form binding sites for bacteria and viruses and are also involved in recognition process by the immune system. Currently, the recently heavily investigated area of protein-saccharide interactions has a great potential of use in the field of drug design. Understanding of protein-carbohydrate interactions enables the glycomimetics development, e.g. small-molecule drugs that can inhibit interaction between he carbohydrte-binding protein and its receptor.

The contribution will be focused on lectins from human opportunistic pathogens, which display sub‑micromolar range affinity towards their carbohydrate ligands. The combination of binding experiments (isothermal titration microcalorimetry, surface plasmon resonance,...) and X-ray crystallography approaches is used to decipher the thermodynamical and structural basis for high affinity binding of these lectins to host carbohydrates. Several examples of different approaches how to proteins from pathogens can reach the high affinities even toward monosaccharides will be discussed. This knowledge is important for the molecular design of potent anti-adhesion therapeutics.

Acknowledgements.

The research has been supported by Ministry of Education of the Czech Republic (MSM0021622413, LC06030, ME08008), Grant Agency of the Czech Republic (303/09/1168) and the European Community's Seventh Framework Program under grant agreement n° 205872.