The First Protein-Carbohydrate Interaction Inhibitor

Immunomodulation is all the rage, particularly in terms of cancer.  Hyaluronan (HA) is a component of the extracellular matrix.  CD44 is a major cell receptor of HA and its fragments.  Its differential response to HA or HA fragments leads to the different biologies. However, due to the different biologies there are limitations to what can be done with HA fragments.  A selective inhibitor of CD44-HA would prove an invaluable tool. Also, in the grandest of Grant-Application-ese, a small molecule inhibitor could be useful for inflammatory diseases and cancer.  

In this paper, results are presented towards this goal.  The hyaluronan-binding domain (HABD) of CD44 is competent to bind oligosaccharides, and even better has been crystallized. In terms of the binding site:

From the structural data, one might conclude that CD44 is not an easily druggable target. The murine HABD−HA complex reveals an extended HA binding site with surface area exceeding 800 Å^2 and molecular binding stabilized by a large number of weak interactions involving at least seven consecutive saccharide units of HA. The HABD has no well formed or deep pockets that would serve as attractive binding sites for small molecule inhibitors and is known to undergo small but important conformational changes upon binding HA. In many respects, the protein−polysaccharide complex resembles protein−protein interactions that are difficult to disrupt effectively with small molecules.

Using SPR, they screened 1000 fragments from the Maybridge Ro3 fragment library at 5 mM resulting in a 4% hit rate. 21 fragments were crystallized (Table 3 in SI), resulting in 5 co-crystals.  Cpds 1 and 2 were deemed worthy based upon their binding site. 

They were poor in terms of blocking HA binding to CD44.  So, they then did some Analog by Catalog and some merging, based upon other scaffolds and ended up with 5a, which has improved affinity for the HABD and had a measurable ability to block HA binding to the HABD.  

This is a interesting paper to me simply because of the target choice:protein-carbohydrate interaction.  I believe this is the first example of FBHG against a PCI.