Small molecule inhibitors of protein interaction with glycosaminoglycans (SMIGs), a novel class of bioactive agents with anti-inflammatory properties

• Published in: Biochimica et biophysica acta Vol. 1840; no. 1; pp. 245 - 254
• Main Authors: Harris, Nicholas, Kogan, Faina Yurgenzon, Il'kova, Gabriela, Juhas, Stefan, Lahmy, Orly, Gregor, Yevgeniya I., Koppel, Juraj, Zhuk, Regina, Gregor, Paul
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2014
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Carrageenan - toxicity; Cattle; Chemokines - metabolism; Cytokine; Cytokines - metabolism; Edema - chemically induced; Edema - drug therapy; Edema - metabolism; Glycosaminoglycan; Glycosaminoglycans - metabolism; Heparan sulfate; Heparin - metabolism; Heparin binding protein; Heparitin Sulfate - metabolism; High-Throughput Screening Assays; Humans; Hypersensitivity, Delayed; Immunoglobulin G - metabolism; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Inflammation - pathology; L-selectin; L-Selectin - metabolism; Leukocytes - drug effects; Leukocytes - metabolism; Leukocytes - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Molecular Structure; Neutrophils - drug effects; Neutrophils - metabolism; Neutrophils - pathology; Protein Binding; Protein Interaction Domains and Motifs - drug effects; Small Molecule Libraries; SMIG or SMIGs; Heparan sulfate; VEGF; Cytokine; DTH; Heparin binding protein; Glycosaminoglycan; L-selectin; Inflammation; GAG; HS-GAG; small molecule inhibitors of protein interaction with glycosaminoglycans; delayed-type hypersensitivity; vascular endothelial growth factor
• ISSN: 0304-4165; 0006-3002; 1872-8006; 1878-2434
• DOI: 10.1016/j.bbagen.2013.09.023

Small molecule inhibitors of biologically important protein–glycosaminoglycan (GAG) interactions have yet to be identified. Compound libraries were screened in an assay of L-selectin–IgG binding to heparin (a species of heparan sulfate [HS-GAG]). Hits were validated, IC-50s established and direct binding of hits to HS-GAGs was investigated by incubating compounds alone with heparin. Selectivity of inhibitors was assessed in 11 different protein-GAG binding assays. Anti-inflammatory activity of selected compounds was evaluated in animal models. Screening identified a number of structurally-diverse planar aromatic cationic amines. Scaffolds similar to known GAG binders, chloroquine and tilorone, were also identified. Inhibitors displayed activity also against bovine kidney heparan sulfate. Direct binding of compounds to GAGs was verified by incubating compounds with heparin alone. Selectivity of inhibitors was demonstrated in a panel of 11 heparin binding proteins, including selectins, chemokines (IL-8, IP-10), Beta Amyloid and cytokines (VEGF, IL-6). A number of selected lead compounds showed dose-dependent efficacy in peritonitis, paw edema and delayed type hypersensitivity. A new class of compounds, SMIGs, inhibits protein–GAG interaction by direct binding to GAGs. Although their IC-50s were in the low micro-molar range, SMIGs binding to HS-GAGs appeared to be stable in physiological conditions, indicating high avidity binding. SMIGs may interfere with major checkpoints for inflammatory and autoimmune events. SMIGs are a class of structurally-diverse planar aromatic cationic amines that have an unusual mode of action — inhibiting protein–GAG interactions via direct and stable binding to GAGs. SMIGs may have therapeutic potential in inflammatory and autoimmune disorders. •Compounds (SMIGs) that bind directly to glycosaminoglycans (GAGs) are described.•SMIGs are small molecule inhibitors of protein interaction with GAGs.•SMIGs inhibit selectin, chemokine and cytokine binding to GAGs.•SMIGs are structurally-diverse aromatic cationic amines that bind to GAGs stably.•SMIGs have anti-inflammatory properties and might be useful as therapeutics.