Identification of ALEKSIN as a novel multi-IRF inhibitor of IRF- and STAT-mediated transcription in vascular inflammation and atherosclerosis
Cardiovascular diseases (CVDs) include atherosclerosis, which is an inflammatory disease of large and medium vessels that leads to atherosclerotic plaque formation. The key factors contributing to the onset and progression of atherosclerosis include the pro-inflammatory cytokines interferon (IFN)α a...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1471182/full |
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| author | Aleksandra Antonczyk Katarzyna Kluzek Natalia Herbich Mahdi Eskandarian Boroujeni Bart Krist Dorota Wronka Anna Karlik Lukasz Przybyl Adam Plewinski Joanna Wesoly Hans A. R. Bluyssen |
| author_facet | Aleksandra Antonczyk Katarzyna Kluzek Natalia Herbich Mahdi Eskandarian Boroujeni Bart Krist Dorota Wronka Anna Karlik Lukasz Przybyl Adam Plewinski Joanna Wesoly Hans A. R. Bluyssen |
| author_sort | Aleksandra Antonczyk |
| collection | DOAJ |
| description | Cardiovascular diseases (CVDs) include atherosclerosis, which is an inflammatory disease of large and medium vessels that leads to atherosclerotic plaque formation. The key factors contributing to the onset and progression of atherosclerosis include the pro-inflammatory cytokines interferon (IFN)α and IFNγ and the pattern recognition receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger the activation of IFN regulatory factors (IRFs) and signal transducer and activator of transcription (STAT)s. Based on their promoting role in atherosclerosis, we hypothesized that the inhibition of pro-inflammatory target gene expression through multi-IRF inhibitors may be a promising strategy to treat CVDs. Using comparative in silico docking of multiple IRF–DNA-binding domain (DBD) models on a multi-million natural compound library, we identified the novel multi-IRF inhibitor, ALEKSIN. This compound targets the DBD of IRF1, IRF2, and IRF8 with the same affinity and simultaneously inhibits the expression of multiple IRF target genes in human microvascular endothelial cells (HMECs) in response to IIFNα and IFNγ. Under the same conditions, ALEKSIN also inhibited the phosphorylation of STATs, potentially through low-affinity STAT-SH2 binding but with lower potency than the known multi-STAT inhibitor STATTIC. This was in line with the common inhibition of ALEKSIN and STATTIC observed on the genome-wide expression of pro-inflammatory IRF/STAT/NF-κB target genes, as well as on the migration of HMECs. Finally, we identified a novel signature of 46 ALEKSIN and STATTIC commonly inhibited pro-atherogenic target genes, which was upregulated in atherosclerotic plaques in the aortas of high-fat diet-fed ApoEKO mice and associated with inflammation, proliferation, adhesion, chemotaxis, and response to lipids. Interestingly, the majority of these genes could be linked to macrophage subtypes present in aortic plaques in HFD-fed LDLR-KO mice. Together, this suggests that ALEKSIN represents a novel class of multi-IRF inhibitors, which inhibits IRF-, STAT-, and NF-κB-mediated transcription and could offer great promise for the treatment of CVDs. Furthermore, the ALEKSIN and STATTIC commonly inhibited pro-inflammatory gene signature could help monitor plaque progression during experimental atherosclerosis. |
| format | Article |
| id | doaj-art-9060faaaa6aa4aa88d5bda4a9cc2dd3d |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-9060faaaa6aa4aa88d5bda4a9cc2dd3d2025-01-07T06:41:01ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-01-011510.3389/fphar.2024.14711821471182Identification of ALEKSIN as a novel multi-IRF inhibitor of IRF- and STAT-mediated transcription in vascular inflammation and atherosclerosisAleksandra Antonczyk0Katarzyna Kluzek1Natalia Herbich2Mahdi Eskandarian Boroujeni3Bart Krist4Dorota Wronka5Anna Karlik6Lukasz Przybyl7Adam Plewinski8Joanna Wesoly9Hans A. R. Bluyssen10Human Molecular Genetics Research Unit, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, PolandHuman Molecular Genetics Research Unit, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, PolandHuman Molecular Genetics Research Unit, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, PolandHuman Molecular Genetics Research Unit, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, PolandHuman Molecular Genetics Research Unit, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, PolandLaboratory of Mammalian Model Organisms, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, PolandLaboratory of Mammalian Model Organisms, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, PolandLaboratory of Mammalian Model Organisms, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, PolandAnimal Facility, Center for Advanced Technologies, Adam Mickiewicz University, Poznan, PolandLaboratory of High Throughput Technologies, Faculty of Biology, Adam Mickiewicz University, Poznan, PolandHuman Molecular Genetics Research Unit, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, PolandCardiovascular diseases (CVDs) include atherosclerosis, which is an inflammatory disease of large and medium vessels that leads to atherosclerotic plaque formation. The key factors contributing to the onset and progression of atherosclerosis include the pro-inflammatory cytokines interferon (IFN)α and IFNγ and the pattern recognition receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger the activation of IFN regulatory factors (IRFs) and signal transducer and activator of transcription (STAT)s. Based on their promoting role in atherosclerosis, we hypothesized that the inhibition of pro-inflammatory target gene expression through multi-IRF inhibitors may be a promising strategy to treat CVDs. Using comparative in silico docking of multiple IRF–DNA-binding domain (DBD) models on a multi-million natural compound library, we identified the novel multi-IRF inhibitor, ALEKSIN. This compound targets the DBD of IRF1, IRF2, and IRF8 with the same affinity and simultaneously inhibits the expression of multiple IRF target genes in human microvascular endothelial cells (HMECs) in response to IIFNα and IFNγ. Under the same conditions, ALEKSIN also inhibited the phosphorylation of STATs, potentially through low-affinity STAT-SH2 binding but with lower potency than the known multi-STAT inhibitor STATTIC. This was in line with the common inhibition of ALEKSIN and STATTIC observed on the genome-wide expression of pro-inflammatory IRF/STAT/NF-κB target genes, as well as on the migration of HMECs. Finally, we identified a novel signature of 46 ALEKSIN and STATTIC commonly inhibited pro-atherogenic target genes, which was upregulated in atherosclerotic plaques in the aortas of high-fat diet-fed ApoEKO mice and associated with inflammation, proliferation, adhesion, chemotaxis, and response to lipids. Interestingly, the majority of these genes could be linked to macrophage subtypes present in aortic plaques in HFD-fed LDLR-KO mice. Together, this suggests that ALEKSIN represents a novel class of multi-IRF inhibitors, which inhibits IRF-, STAT-, and NF-κB-mediated transcription and could offer great promise for the treatment of CVDs. Furthermore, the ALEKSIN and STATTIC commonly inhibited pro-inflammatory gene signature could help monitor plaque progression during experimental atherosclerosis.https://www.frontiersin.org/articles/10.3389/fphar.2024.1471182/fullinterferon regulatory factorsignal transducer and activator of transcriptioninterferonToll-like receptorvascular inflammationin silico docking |
| spellingShingle | Aleksandra Antonczyk Katarzyna Kluzek Natalia Herbich Mahdi Eskandarian Boroujeni Bart Krist Dorota Wronka Anna Karlik Lukasz Przybyl Adam Plewinski Joanna Wesoly Hans A. R. Bluyssen Identification of ALEKSIN as a novel multi-IRF inhibitor of IRF- and STAT-mediated transcription in vascular inflammation and atherosclerosis Frontiers in Pharmacology interferon regulatory factor signal transducer and activator of transcription interferon Toll-like receptor vascular inflammation in silico docking |
| title | Identification of ALEKSIN as a novel multi-IRF inhibitor of IRF- and STAT-mediated transcription in vascular inflammation and atherosclerosis |
| title_full | Identification of ALEKSIN as a novel multi-IRF inhibitor of IRF- and STAT-mediated transcription in vascular inflammation and atherosclerosis |
| title_fullStr | Identification of ALEKSIN as a novel multi-IRF inhibitor of IRF- and STAT-mediated transcription in vascular inflammation and atherosclerosis |
| title_full_unstemmed | Identification of ALEKSIN as a novel multi-IRF inhibitor of IRF- and STAT-mediated transcription in vascular inflammation and atherosclerosis |
| title_short | Identification of ALEKSIN as a novel multi-IRF inhibitor of IRF- and STAT-mediated transcription in vascular inflammation and atherosclerosis |
| title_sort | identification of aleksin as a novel multi irf inhibitor of irf and stat mediated transcription in vascular inflammation and atherosclerosis |
| topic | interferon regulatory factor signal transducer and activator of transcription interferon Toll-like receptor vascular inflammation in silico docking |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1471182/full |
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