1. Synthetic 1,2,3-triazole-linked glycoconjugates bind with high affinity to human galectin-3
- Author
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João Francisco Pereira, Vanessa Leiria Campo, Marcelo Fiori Marchiori, Richard D. Cummings, Lauro T. Kubota, Dênio Emanuel Pires Souto, Ivone Carvalho, Leandro Oliveira Bortot, and Marcelo Dias-Baruffi
- Subjects
Azides ,1,2,3-Triazole ,Molecular model ,Glycoconjugate ,Stereochemistry ,Galectin 3 ,Galectins ,Clinical Biochemistry ,Triazole ,Pharmaceutical Science ,Lactose ,Molecular Dynamics Simulation ,Ligands ,Biochemistry ,Divalent ,chemistry.chemical_compound ,Drug Discovery ,Humans ,Amino Acids ,Surface plasmon resonance ,Molecular Biology ,chemistry.chemical_classification ,Cycloaddition Reaction ,Organic Chemistry ,MODELAGEM MOLECULAR ,Galactosides ,Blood Proteins ,Triazoles ,Amino acid ,Molecular Docking Simulation ,chemistry ,Alkynes ,Click chemistry ,Molecular Medicine ,Click Chemistry ,Glycoconjugates ,Protein Binding - Abstract
This work describes the synthesis of the 1,2,3-triazole amino acid-derived-3-O-galactosides 1-6 and the 1,2,3-triazole di-lactose-derived glycoconjugate 7 as potential galectin-3 inhibitors. The target compounds were synthesized by Cu(I)-catalyzed azide-alkyne cycloaddition reaction ('click chemistry') between the azido-derived amino acids N3-ThrOBn, N3-PheOBn, N3-N-Boc-TrpOBn, N3-N-Boc-LysOBn, N3-O-tBu-AspOBn and N3-l-TyrOH, and the corresponding alkyne-based sugar 3-O-propynyl-GalOMe, as well as by click chemistry reaction between the azido-lactose and 2-propynyl lactose. Surface plasmon resonance (SPR) assays showed that all synthetic glycoconjugates 1-7 bound to galectin-3 with high affinity, but the highest binders were the amino acids-derived glycoconjugates 2 (KD 7.96μM) and 4 (KD 4.56μM), and the divalent lactoside 7 (KD1 0.15μM/KD2 19μM). Molecular modeling results were in agreement with SPR assays, since more stable interactions with galectin-3 were identified for glycoconjugates 2, 4 and 7. Regarding compounds 2 and 4, they established specific cation-π (Arg144) and ionic (Asp148) interactions, whereas glycoconjugate 7 was capable to bridge two independent galectin-3 CRDs, creating a non-covalent cross-link between two monomers and, thus, reaching a submicromolar affinity towards galectin-3.
- Published
- 2015
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