Designing small high affinity lectin inhibitors starting from natural saccharides is a major challenge due to their polarity and that the matching lectin binding sites not only are polar but also shallow. The lectin/ligand interactions are often made up by complex hydrogen networks which in some cases are strengthened by other interactions such as CH-π stacking between the ligand carbohydrate skeleton and aromatic aminoacids. Therefore, natural mono- and disaccharides in general have low binding affinites in the µM-mM range. Polar ligands like saccharides in general also have low passive uptake over the intestine and often rapid renal or biliary excretion. Despite these challenges several ligands targeting carbohydrate binding sites of different target classes have been discovered and developed into medicines. Examples are the heparin mimetic fondaparinux, the glifozins which are glucose transporter inhibitors (SGLT2), inhibitors of the uropathic E. coliadhesin FimH,influenza neuramnidase inhibitors zanamivir and oseltamivir, selectin inhibitors, siglec inhibitors and the iminosugar miglastat, which last year was approved by FDA for treatment of Fabry disease. We have developed small high affinity carbohydrate-based ligands targeting galectin 3, a target involved in the pathology of inflammation and fibrosis. Our first inhibitor TD139 is currently in phase IIb trials, being developed as an inhaled treatment of idiopatic pulmonary fibrosis (IPF). Recently we discovered an orally available galectin 3 inhibitor GB1211 which has been taken into phase 1 clinical trials in healthy volunteers targeting non-alcoholic steatohepatitis (NASH). This presentation will discuss learnings from the design of ligands targeting carbohydrate binding sites with examples from both our own galectin research and literature.

Design of ligands targeting carbohydrate binding sites: Galectin 3

2019 Fall National Meeting

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