New, Low–Molecular Weight Chemical Compounds Inhibiting Biological Activity of Interleukin 15
Chronic overproduction of IL–15 contributes to the pathogenesis of numerous inflammatory and autoimmune disorders. Experimental methods used to reduce the cytokine activity show promise as potential therapeutic approaches to modify IL–15 signaling and alleviate the development and progression of IL–...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/5/2287 |
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| author | Piotr Krzeczyński Małgorzata Dutkiewicz Oliwia Zegrocka-Stendel Bartosz Trzaskowski Katarzyna Koziak |
| author_facet | Piotr Krzeczyński Małgorzata Dutkiewicz Oliwia Zegrocka-Stendel Bartosz Trzaskowski Katarzyna Koziak |
| author_sort | Piotr Krzeczyński |
| collection | DOAJ |
| description | Chronic overproduction of IL–15 contributes to the pathogenesis of numerous inflammatory and autoimmune disorders. Experimental methods used to reduce the cytokine activity show promise as potential therapeutic approaches to modify IL–15 signaling and alleviate the development and progression of IL–15–related diseases. We previously demonstrated that an efficient reduction of IL–15 activity can be obtained by selective blocking of the specific, high affinity subunit alpha of the IL–15 receptor (IL–15Rα) with small–molecule inhibitors. In this study, we determined the structure–activity relationship of currently known IL–15Rα inhibitors in order to define the critical structural features required for their activity. To validate our predictions, we designed, analyzed in silico, and assessed in vitro function of 16 new potential IL–15Rα inhibitors. All newly synthesized molecules were benzoic acid derivatives with favorable ADME properties and they efficiently reduced IL–15 dependent peripheral blood mononuclear cells (PBMCs) proliferation, as well as TNF–α and IL–17 secretion. The rational design of IL–15 inhibitors may propel the identification of potential lead molecules for the development of safe and effective therapeutic agents. |
| first_indexed | 2024-03-11T07:16:16Z |
| format | Article |
| id | doaj.art-2a98d1ea246c42bb843940285b37cda0 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T07:16:16Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-2a98d1ea246c42bb843940285b37cda02023-11-17T08:14:35ZengMDPI AGMolecules1420-30492023-03-01285228710.3390/molecules28052287New, Low–Molecular Weight Chemical Compounds Inhibiting Biological Activity of Interleukin 15Piotr Krzeczyński0Małgorzata Dutkiewicz1Oliwia Zegrocka-Stendel2Bartosz Trzaskowski3Katarzyna Koziak4Chemistry Section, Pharmacy, Cosmetic Chemistry and Biotechnology Research Group, Łukasiewicz Research Network–Industrial Chemistry Institute, Rydygiera 8, 01-793 Warsaw, PolandDepartment of Biochemistry and Nutrition, Centre for Preclinical Research and Technologies, Medical University of Warsaw, S. Banacha1b, 02-097 Warsaw, PolandDepartment of Biochemistry and Nutrition, Centre for Preclinical Research and Technologies, Medical University of Warsaw, S. Banacha1b, 02-097 Warsaw, PolandCentre of New Technologies, University of Warsaw, S. Banacha 2c, 02-097 Warsaw, PolandDepartment of Biochemistry and Nutrition, Centre for Preclinical Research and Technologies, Medical University of Warsaw, S. Banacha1b, 02-097 Warsaw, PolandChronic overproduction of IL–15 contributes to the pathogenesis of numerous inflammatory and autoimmune disorders. Experimental methods used to reduce the cytokine activity show promise as potential therapeutic approaches to modify IL–15 signaling and alleviate the development and progression of IL–15–related diseases. We previously demonstrated that an efficient reduction of IL–15 activity can be obtained by selective blocking of the specific, high affinity subunit alpha of the IL–15 receptor (IL–15Rα) with small–molecule inhibitors. In this study, we determined the structure–activity relationship of currently known IL–15Rα inhibitors in order to define the critical structural features required for their activity. To validate our predictions, we designed, analyzed in silico, and assessed in vitro function of 16 new potential IL–15Rα inhibitors. All newly synthesized molecules were benzoic acid derivatives with favorable ADME properties and they efficiently reduced IL–15 dependent peripheral blood mononuclear cells (PBMCs) proliferation, as well as TNF–α and IL–17 secretion. The rational design of IL–15 inhibitors may propel the identification of potential lead molecules for the development of safe and effective therapeutic agents.https://www.mdpi.com/1420-3049/28/5/2287IL–15IL–15Rαsmall–molecule IL–15Rα inhibitorbenzoic acid |
| spellingShingle | Piotr Krzeczyński Małgorzata Dutkiewicz Oliwia Zegrocka-Stendel Bartosz Trzaskowski Katarzyna Koziak New, Low–Molecular Weight Chemical Compounds Inhibiting Biological Activity of Interleukin 15 Molecules IL–15 IL–15Rα small–molecule IL–15Rα inhibitor benzoic acid |
| title | New, Low–Molecular Weight Chemical Compounds Inhibiting Biological Activity of Interleukin 15 |
| title_full | New, Low–Molecular Weight Chemical Compounds Inhibiting Biological Activity of Interleukin 15 |
| title_fullStr | New, Low–Molecular Weight Chemical Compounds Inhibiting Biological Activity of Interleukin 15 |
| title_full_unstemmed | New, Low–Molecular Weight Chemical Compounds Inhibiting Biological Activity of Interleukin 15 |
| title_short | New, Low–Molecular Weight Chemical Compounds Inhibiting Biological Activity of Interleukin 15 |
| title_sort | new low molecular weight chemical compounds inhibiting biological activity of interleukin 15 |
| topic | IL–15 IL–15Rα small–molecule IL–15Rα inhibitor benzoic acid |
| url | https://www.mdpi.com/1420-3049/28/5/2287 |
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