Targeting osteoarthritis-associated galectins and an induced effector class by a ditopic bifunctional reagent: Impact of its glycan part on binding measured in the tissue context. (1st December 2022)

• Record Type: Journal Article
• Authors: Manning, Joachim C.; Baldoneschi, Veronica; Romero-Hernández, Laura L.; Pichler, Katharina M.; GarcÍa Caballero, Gabriel; André, Sabine; Kutzner, Tanja J.; Ludwig, Anna-Kristin; Zullo, Valerio; Richichi, Barbara; Windhager, Reinhard; Kaltner, Herbert; Toegel, Stefan; Gabius, Hans-Joachim; Murphy, Paul V.; Nativi, Cristina
• Is Part Of: Bioorganic & medicinal chemistry. Volume 75(2022)
• Publication Date: 2022-12-01
• Subjects: Cartilage -- Glycocluster -- Lectin -- Matrix metalloproteinase -- Osteoarthritis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.117068
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Bivalency is integrated into a heterobifunctional galectin inhibitor. Testing this lectin inhibitor on a tissue-based platform is optimized. 2-Colour fluorescence microscopy determines relative inhibitory capacity. Analysis of clinical specimens opens biomedical perspectives. Abstract: Pairing glycans with tissue lectins controls multiple effector pathways in (patho)physiology. A clinically relevant example is the prodegradative activity of galectins-1 and -3 (Gal-1 and -3) in the progression of osteoarthritis (OA) via matrix metalloproteinases (MMPs), especially MMP-13. The design of heterobifunctional inhibitors that can block galectin binding and MMPs both directly and by preventing their galectin-dependent induction selectively offers a perspective to dissect the roles of lectins and proteolytic enzymes. We describe the synthesis of such a reagent with a bivalent galectin ligand connected to an MMP inhibitor and of two tetravalent glycoclusters with a subtle change in headgroup presentation for further elucidation of influence on ligand binding. Testing was performed on clinical material with mixtures of galectins as occurring in vivo, using sections of fixed tissue. Two-colour fluorescence microscopy monitored binding to the cellular glycome after optimization of experimental parameters. In the presence of the inhibitor, galectin binding to OA specimens was significantly reduced. These results open the perspective to examine the inhibitory capacity of custom-made ditopic compounds on binding of lectins in mixtures using sections of clinical material with known impact of galectins and MMPs on disease progression.