title: From a library of MAG antagonists to nanomolar CD22 ligands.
abstract: Siglec-2, also known as CD22, is involved in the regulation and survival of B-cells and has been successfully targeted in cell depletion therapies with antibody-based approaches. Sialic acid derivatives, already known to bind with high affinity to myelin-associated glycoprotein (MAG, Siglec-4), were screened for their binding affinity for CD22 by surface plasmon resonance. The best compound identified was further modified with various hydrophobic substituents at the 2-, 5-, and 9-positions of the sialic acid scaffold, leading to nanomolar derivatives, of which ligand 17 b shows the most promising pharmacodynamic and pharmacokinetic profiles. Isothermal titration calorimetry measurements demonstrate that the binding is enthalpy driven. Interestingly, the thermodynamic fingerprints reveal an excellent correlation between gains in enthalpy and compensation by increased entropy costs. Moreover, 17 b exhibits a residence time in the range of a few seconds, clearly prolonged relative to residence times typically observed for carbohydrate-lectin interactions. Finally, initial tests regarding drug-like properties of 17 b demonstrate the required high plasma protein binding yet a lack of oral availability, although its distribution coefficient (log D) is in the required range.
authors: Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Basel, Switzerland.
authors: Stefanie
authors: S
authors: Mesch
authors: Katrin
authors: K
authors: Lemme
authors: Matthias
authors: M
authors: Wittwer
authors: Hendrik
authors: H
authors: Koliwer-Brandl
authors: Oliver
authors: O
authors: Schwardt
authors: Sørge
authors: S
authors: Kelm
authors: Beat
authors: B
authors: Ernst
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors*; D019158:N-Acetylneuraminic Acid / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D020349:Surface Plasmon Resonance; D013816:Thermodynamics
chemical_list: D001798:Blood Proteins; D008024:Ligands; D018992:Myelin-Associated Glycoprotein; D051918:Sialic Acid Binding Ig-like Lectin 2; D054852:Small Molecule Libraries; D019158:N-Acetylneuraminic Acid