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Suramin is a symmetric polysulfonated naphthylamine-benzamide urea derivative approved for the treatment of trypanosomiasis and onchocerciasis and a known P2 (ATP/UTP purine receptor) antagonist. Here, we report its ability to inhibit the important CD40-CD154 costimulatory interaction required for T cell activation and the development of an effective immune response. In vitro, it inhibited the binding of both human and murine CD154 (CD40L) to their receptor (CD40) even in the presence of protein-containing media and prevented the CD154-induced proliferation of human B cells as well as the corresponding increase in surface expression of CD86, CD80, CD40, and MHC class II in a concentration-dependent manner. Furthermore, in isolated human islets, it also decreased the CD154-induced release of inflammatory cytokines such as IFN-γ, interleukin-6 (IL-6), and IL-8. Suramin was selected for investigation because it has been reported to be an inhibitor of the interaction of TNF-α with its receptor and CD154 is a member of the TNF-family. However, it turned out to be a considerably, about 30-fold, more effective inhibitor of the CD40-CD154 protein-protein interaction than of the corresponding TNF interaction. Its median inhibitory concentration (IC50 ≈ 50 μM) is somewhat higher than for the P2-receptor, but well within the range of its therapeutic concentration levels. Suramin shows considerable polypharmacology, but its interference with the positive costimulatory interaction might provide a possible, not yet identified mechanism for its ability to suppress T cell activity and induce immunosuppression, which might also have limited its clinical usefulness in the treatment of AIDS and cancer.