1. Design of a peptidic inhibitor that targets the dimer interface of a prototypic galectin.
- Author
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Vladoiu MC, Labrie M, Létourneau M, Egesborg P, Gagné D, Billard É, Grosset AA, Doucet N, Chatenet D, and St-Pierre Y
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Apoptosis drug effects, Blotting, Western, Galectins chemistry, Galectins genetics, Humans, Jurkat Cells, Models, Molecular, Peptides chemical synthesis, Protein Binding, Protein Structure, Quaternary, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Recombinant Proteins pharmacology, Drug Design, Galectins antagonists & inhibitors, Peptides pharmacology, Protein Multimerization drug effects
- Abstract
Galectins are small soluble lectins that bind α-galactosides via their carbohydrate recognition domain (CRD). Their ability to dimerize is critical for the crosslinking of glycoprotein receptors and subsequent cellular signaling. This is particularly important in their immunomodulatory role via the induction of T-cell apoptosis. Because galectins play a central role in many pathologies, including cancer, they represent valuable therapeutic targets. At present, most inhibitors have been directed towards the CRD, a challenging task in terms of specificity given the high structural homology of the CRD among galectins. Such inhibitors are not effective at targeting CRD-independent functions of galectins. Here, we report a new class of galectin inhibitors that specifically binds human galectin-7 (hGal-7), disrupts the formation of homodimers, and inhibits the pro-apoptotic activity of hGal-7 on Jurkat T cells. In addition to representing a new means to achieve specificity when targeting galectins, such inhibitors provide a promising alternative to more conventional galectin inhibitors that target the CRD with soluble glycans or other small molecular weight allosteric inhibitors.
- Published
- 2015
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