Galectin-1 is overexpressed in malignant tissues and
involved in numerous types of cancer.[1] The prominent member of
animal lectins forms a homodimeric structure with characteristic
carbohydrate-recognition domains on opposite sites. Interactions with ß
-galactosides
(like lactose and N-acetyllactosamine)
of glycoconjugates on cell surfaces introduce biomolecular processes like cell growth,
apoptosis, immune reactions and tumor progression.[2, 3] However,
the affinity towards natural carbohydrates is low with Kd values in the high micromolar range.
Although the identification of an increased level of galectin-1
in patients is a strong indication for cancer, its mechanism and function in
cancer progression remains unclear. High affine ligands of galectin-1 would hereby
enable to follow the interaction on cellular level and may in future lead to
new cancer diagnosis and therapies.
For the ligand development we first produced our
target human galectin-1 by overexpression in E.coli. Further docking studies of “reactive” ß-galactosides
candidates (lactose and N-acetyllactosamine)
with the X-ray structure of the protein paved the way for the rational
galectin-1 inhibitor design. Cocrystallization experiments of galectin-1 and these
carbohydrate precursors confirmed the computational drug-design studies. The
lecture disputes a possible path for galectin-1 drug development from the first
sketch over proposing a candidate by the computational drug
design, the synthetic realization, protein-structure analysis to the final drug
candidate.
[1] Smetana Jr, K.; André, S.; Kaltner, H.; Kopitz, J.; Gabius, H.-J. Expert Opin. Ther. Targets 2013, doi: 10.1517/14728222.2013.750651.
[2] Rabinovich, G. A.; Toscano, M. A. Nat. Rev. Immunol. 2009, 9 (5), 338-352.
[3] Vasta, G. R. Nat. Rev. Microbiol. 2009, 7 (6), 424-438.
