Pharmacophore guided discovery of small-molecule interleukin 15 inhibitors

The anti-inflammatory potential of cefazolin as common gamma chain cytokine inhibitor

“…Two potential binding sites of very high binding affinities for cefazolin were revealed by molecular docking in each of the receptor subunits (K i of 72/87 pM and 70/79 pM for IL2/IL-15Rβ and γ c , respectively). These values are lower than our previously reported estimates of cefazolin binding affinity to IL-15Rα which suggests that the drug binds preferentially to IL-2/IL-15Rβ and/or γ c 5 . Both of the cefazolin binding sites in IL-2/IL-15Rβ chain are located relatively far from the γ c and the cytokine.…”

“…Reduction in IL-2, IL-4 and IL-15-induced cell proliferation caused by cefazolin, although not robust, suggests that the drug interferes not only with IL-15Rα, as reported previously 5 , but also with IL-2/IL-15Rβ and/or γ c .…”

“…Advances in crystallography and in silico techniques provide promising opportunities in the design of protein-protein interaction inhibitors for therapeutic purposes 17 . Detailed information about the 3D structure and molecular determinants of the specific, high affinity interaction between IL-15 and IL-15Rα 18,19 , combined with docking and experimental methods resulted in our recent discovery of cefazolin -an old, safe first-generation cephalosporin antibiotic, as promising IL-15Rα inhibitor 5 . In the present study we used broader approach to determine cefazolin potential to interfere with the two other IL-15R subunits: the IL-2/IL-15Rβ, which is shared with IL-2, and the γ c -a common component of receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.…”

“…In a recent study, BNZ-1 -a pegylated peptide designed to specifically bind the γ c receptor and to selectively block IL-2, IL-15, and IL-9 signaling -was demonstrated to inhibit cytokine-mediated cell viability and downstream signaling as well as to increase apoptosis in T-cell large granular lymphocyte leukemia (T-LGLL) cell line and in cells obtained from T-LGLL patients 39 . The collection of newly discovered IL-15 antagonists contains also small-molecule inhibitors of IL-15, IL-15Rα and IL-2/IL-15Rβ identified in vitro studies performed by our group 5 and by others 40 . Their biological effect was demonstrated as suppression of IL-15 dependent IL-17 and TNF-α production 5 and cell proliferation 40 .…”

“…The collection of newly discovered IL-15 antagonists contains also small-molecule inhibitors of IL-15, IL-15Rα and IL-2/IL-15Rβ identified in vitro studies performed by our group 5 and by others 40 . Their biological effect was demonstrated as suppression of IL-15 dependent IL-17 and TNF-α production 5 and cell proliferation 40 . It should be noted that γ c family cytokines receptor subunits may exert their regulatory effects not only as membrane receptors but also as secreted proteins.…”