Targeting the CRD F-face of Human Galectin-3 and Allosterically Modulating Glycan Binding by Angiostatic PTX008 and a Structurally Optimized Derivative

Calix[4]arene PTX008 is an angiostatic agent that inhibits tumor growth in mice by binding to galectin-1, a b-galactoside-binding lectin. To assess the affinity profile of PTX008 for galectins, we used 15N–1H HSQC NMRspectroscopy to show that PTX008 also binds to galectin-3 (Gal-3), albeit more weakly. We identified the contact sitefor PTX008 on the F-face of the Gal-3 carbohydrate recognition domain. STD NMR revealed that the hydrophobicphenyl ring crown of the calixarene is the binding epitope