Inhibition of tumor necrosis factor-α (TNF-α)/ TNF-α receptor binding by structural analogues of suramin

• Published in: Biochemical pharmacology 1999-09, Vol.58 (5), p.851-859
• Main Authors: Mancini, Francesca, Toro, Carola Marani, Mabilia, Massimo, Giannangeli, Marilena, Pinza, Mario, Milanese, Claudio
• Format: Article
• Language: English
• Subjects: Antigens, CD - chemistry; Antigens, CD - metabolism; Binding, Competitive; Biological and medical sciences; Cell receptors; Cell structures and functions; Computer Simulation; Evans blue; Fundamental and applied biological sciences. Psychology; Hormone receptors. Growth factor receptors. Cytokine receptors. Prostaglandin receptors; Humans; Models, Molecular; Molecular and cellular biology; molecular modeling; p55 receptor; Protein Conformation; Receptors, Tumor Necrosis Factor - antagonists & inhibitors; Receptors, Tumor Necrosis Factor - chemistry; Receptors, Tumor Necrosis Factor - metabolism; Receptors, Tumor Necrosis Factor, Type I; suramin; Suramin - analogs & derivatives; Suramin - pharmacology; trypan blue; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - chemistry; Tumor Necrosis Factor-alpha - metabolism; tumor necrosis factor-α
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(99)00150-1

Suramin, a symmetrical polysulfonated urea derivative, promotes the dissociation of trimeric human tumor necrosis factor-α (TNF-α) into biologically inactive subunits and prevents the interaction of TNF-α with its cellular receptors. The aim of this work was to identify compounds structurally related to suramin which inhibit the binding of TNF-α to its receptor. Molecular modeling studies were performed on suramin and TNF-α molecules and likely interaction sites were identified in the docked complex. On this basis, Evans blue, trypan blue, sulfonazo III, beryllon II, and 1,3,6-naphthalenetrisulfonic acid trisodium salt were identified as polysulfonated compounds endowed, to various extents, with the structural characteristics responsible for interaction with TNF-α. N, N-bis(3,5-di- tert-butylphenyl)-3,4,9,10-perylenedicarboximide was used as an unrelated structure. The capacity of these molecules to inhibit the binding of TNF-α with its receptor p55 was tested in vitro by means of a specific immunoenzymatic assay using suramin as reference compound. Evans blue and trypan blue inhibited TNF-α/p55 binding with an ic 50 of 0.75 and 1.00 mM, respectively (suramin ic 50: 0.65 mM); no effect was observed with the other molecules. Molecular modeling analyses on Evans blue and trypan blue docked into the TNF-α molecule support these experimental results by demonstrating that these compounds share with suramin a similar binding mode to TNF-α. The results of this work provide a new insight into and useful hints for the design of new chemical entities endowed with a potent and selective activity on TNF-α.