Effects of protein-protein interface disruptors at the ligand of the glucocorticoid-induced tumor necrosis factor receptor-related gene (GITR).
The tumor necrosis factor (TNF) superfamily (TNFSF) includes about thirty structurally related receptors (TNFSFRs) and about twenty protein ligands that bind to one or more of these receptors. Receptors of the tumor necrosis factor (TNF) superfamily (TNFSFRs) are pharmacological targets for treatment of inflammatory and autoimmune diseases. Currently, drugs targeting TNFSFR signaling are biological drugs (monoclonal antibodies, decoy receptors) aimed at binding and sequestering TNFSFR ligands. The glucocorticoid-induced tumor necrosis factor receptor-related gene (GITR) signaling is involved in a series of inflammatory and autoimmune diseases, such as rheumatoid arthritis and Crohn's disease. Our study aimed at repurposing FDA approved small molecules as protein-protein disruptors at the GITR ligand (GITRL) trimer, in order to inhibit the binding of GITRL to its receptor (GITR). A structure based molecular modeling approach was carried out to identify, through high throughput virtual screening, GITRL monomer-monomer disruptors. We used a database of ~8,000 FDA approved drugs, and after virtual screening, we focused on two hit compounds, minocycline and oxytetracycline. These two compounds were tested for their capability to modulate IL-17, IL-21 and RORγT expression in T lymphocytes, isolated from wild-type and GITR knock-out (GITR-/-) mice. Minocycline showed immunomodulatory effects specific to GITR activation and could represent a novel pharmacological tool to treat inflammatory diseases.
['Platania|Chiara Bianca Maria|CBM|', 'Ronchetti|Simona|S|', 'Riccardi|Carlo|C|', 'Migliorati|Graziella|G|', 'Marchetti|Maria Cristina|MC|', 'Di Paola|Luisa|L|', 'Lazzara|Francesca|F|', 'Drago|Filippo|F|', 'Salomone|Salvatore|S|', 'Bucolo|Claudio|C|']
D000818:Animals D000893:Anti-Inflammatory Agents D000911:Antibodies, Monoclonal D001665:Binding Sites D017252:CD3 Complex D005786:Gene Expression Regulation D053450:Glucocorticoid-Induced TNFR-Related Protein D057166:High-Throughput Screening Assays D020381:Interleukin-17 D007378:Interleukins D008297:Male D051379:Mice D018345:Mice, Knockout D008911:Minocycline D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 D010118:Oxytetracycline D061251:Primary Cell Culture D011485:Protein Binding D000072756:Protein Conformation, alpha-Helical D000072757:Protein Conformation, beta-Strand D054730:Protein Interaction Domains and Motifs D013154:Spleen D013601:T-Lymphocytes D048069:Tumor Necrosis Factors
Protein-protein disruptors GITRL Minocycline T lymphocytes Immunomodulation