Design of a peptidic inhibitor that targets the dimer interface of a prototypic galectin

Abstract

Galectins are small soluble lectins that bind β-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.

Intracellular galectin-7 expression in cancer cells results from an autocrine transcriptional mechanism and endocytosis of extracellular galectin-7

“…These findings are of great importance in the design of gal-7 inhibitors for the treatment of various diseases where gal-7 plays a central role, most notably in cancer [ 6 , 7 , 9 ]. These findings suggest that targeting extracellular gal-7 using either CRD-specific inhibitors [ 14 ] or dimer-disrupting peptides (DIPs) [ 13 ] may be more efficient than expected for targeting intracellular gal-7-mediated interactions. Furthermore, our results showing that extracellular gal-7 induces de novo lgals7 gene activation and our approach using FITC-tagged recombinant gal-7 to follow the fate of extracellular gal-7 inside the cells provide new and original in vitro model systems to investigate the inhibitory activity of these gal-7-specific inhibitors.…”

“…Production of human recombinant gal-7 was carried out as described using a pET-22b(+) plasmid encoding a synthetic, codon-optimized cDNA [ 13 ]. In some experiments, recombinant gal-7 was labeled with fluorescein isothiocyanate (FITC) as described [ 13 ]. FITC-labeled gal-7 was purified using a PD-10 Sepharose column (GE healthcare) and eluted with PBS.…”

Galectin‑7 is elevated in endometrioid (type I) endometrial cancer and promotes cell migration

“…Serum galectin-7 concentration is a promising prospective biomarker for predicting subsequent miscarriage or the development of preeclampsia in pregnancy (15,23). Galectin-7 may also have potential as a therapeutic target to treat EC, and inhibitors are currently being developed (38) and could be tested in mouse models of EC. Overall, the present study has identified galectin-7 as a novel mediator of EC progression.…”

Galectins: Key Players at the Frontiers of Innate and Adaptive Immunity

“…Moreover, extracellular Gal7 induced T-cell apoptosis whereas intracellularly this lectin controlled proliferation and differentiation of keratinocytes through mechanisms involving the JNK1, miR-203 and p63 signaling pathways (120)(121)(122). Enforced expression of Gal7 in cancer cells controlled several molecular networks involved in metabolism, survival and immunity (123).…”