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.

Effects of protein-protein interface disruptors at the ligand of the glucocorticoid-induced tumor necrosis factor receptor-related gene (GITR)

Platania C. B. M.;Lazzara F.;Drago F.;Salomone S.;Bucolo C.
2020-01-01

Abstract

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.
2020
GITRL
Immunomodulation
Minocycline
Protein-protein disruptors
T lymphocytes
Animals
Anti-Inflammatory Agents
Antibodies, Monoclonal
Binding Sites
CD3 Complex
Gene Expression Regulation
Glucocorticoid-Induced TNFR-Related Protein
High-Throughput Screening Assays
Interleukin-17
Interleukins
Male
Mice
Mice, Knockout
Minocycline
Nuclear Receptor Subfamily 1, Group F, Member 3
Oxytetracycline
Primary Cell Culture
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Spleen
T-Lymphocytes
Tumor Necrosis Factors
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/496344
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