title: Targeted inhibition of STATs and IRFs as a potential treatment strategy in cardiovascular disease.
abstract: Key factors contributing to early stages of atherosclerosis and plaque development include the pro-inflammatory cytokines Interferon (IFN)α, IFNγ and Interleukin (IL)-6 and Toll-like receptor 4 (TLR4) stimuli. Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT) and Interferon Regulatory Factor (IRF) families. In particular, STAT1, 2 and 3; IRF1 and 8 have recently been recognized as prominent modulators of inflammation, especially in immune and vascular cells during atherosclerosis. Moreover, inflammation-mediated activation of these STATs and IRFs coordinates a platform for synergistic amplification leading to pro-atherogenic responses.Searches for STAT3-targeting compounds, exploring the pTyr-SH2 interaction area of STAT3, yielded many small molecules including natural products. Only a few inhibitors for other STATs, but none for IRFs, are described. Promising results for several STAT3 inhibitors in recent clinical trials predicts STAT3-inhibiting strategies may find their way to the clinic. However, many of these inhibitors do not seem STAT-specific, display toxicity and are not very potent. This illustrates the need for better models, and screening and validation tools for novel STAT and IRF inhibitors.This review presents a summary of these findings. It postulates STAT1, STAT2 and STAT3 and IRF1 and IRF8 as interesting therapeutic targets and targeted inhibition could be a potential treatment strategy in CVDs. In addition, it proposes a pipeline approach that combines comparative in silico docking of STAT-SH2 and IRF-DBD models with in vitro STAT and IRF activation inhibition validation, as a novel tool to screen multi-million compound libraries and identify specific inhibitors for STATs and IRFs.
authors.affiliation: Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Szelag
authors.affiliation: Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Piaszyk-Borychowska
authors.affiliation: Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Martyna
authors.initials: M
authors.lastname: Plens-Galaska
authors.affiliation: Laboratory of High Throughput Technologies, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Wesoly
authors.affiliation: Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Hans A R
authors.initials: HA
authors.lastname: Bluyssen
mesh_terms: D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy / Q000379:methods* / Q000639:trends; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000473:pathology; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; C508600:IL6 protein, human; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D015850:Interleukin-6; D050791:STAT Transcription Factors; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma
keywords: IRF; STAT; in silico modeling; therapeutic strategy; vascular inflammation